Pyrrole and pyrazole DAAO inhibitors

ABSTRACT

Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer&#39;s disease, ataxia or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof:  
                 
wherein 
         R 1  and R 2  are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, and XYR 5 ;    or R 1  and R 2 , taken together, form a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group;    X and Y are independently selected from O, S, NH, and (CR 6 R 7 ) n ;    R 3  is hydrogen, alkyl or M + ; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc ion or a mixture thereof;    Z is N or CR 4 ;    R 4  is from selected from hydrogen, halo, nitro, alkyl, alkylaryl, and XYR 5 ;    R 5  is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;    R 6  and R 7  are independently selected from hydrogen and alkyl; n is an integer from 1 to 6;    at least one of R 1 , R 2  and R 4  is other than hydrogen; and    at least one of X and Y is (CR 6 R 7 ) n . D-serine or cycloserine may be coadministered along with the compound of formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a non-provisional of and claims the benefit of U.S.Provisional Application No. 60/532,979, filed Dec. 29, 2003. The entiredisclosure of U.S. Provisional Application No. 60/532,979is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

The enzyme D-amino acid oxidase (DAAO) metabolizes D-amino acids, and inparticular, metabolizes D-serine in vitro at physiological pH. DAAO isexpressed in the mammalian brain and periphery. D-Serine's role as aneurotransmitter is important in the activation of theN-methyl-D-aspartate (NMDA) selective subtype of the glutamate receptor,an ion channel expressed in neurons, here denoted as NMDA receptor.Small organic molecules, which inhibit the enzymatic cycle of DAAO, maycontrol the levels of D-serine, and thus influence the activity of theNMDA receptor in the brain. NMDA receptor activity is important in avariety of disease states, such as schizophrenia, psychosis, ataxias,ischemia, several forms of pain including neuropathic pain, and deficitsin memory and cognition.

Small organic molecules that inhibit the enzymatic cycle of DAAO mayalso control production of toxic metabolites of D-serine oxidation, suchas hydrogen peroxide and ammonia. Thus, these molecules may influencethe progression of cell loss in neurodegenerative disorders.Neurodegenerative diseases are diseases in which CNS neurons and/orperipheral neurons undergo a progressive loss of function, usuallyaccompanied by (and perhaps caused by) a physical deterioration of thestructure of either the neuron itself or its interface with otherneurons. Such conditions include Parkinson's disease, Alzheimer'sdisease, Huntington's disease and neuropathic pain. N-methyl-D-aspartate(NMDA)-glutamate receptors are expressed at excitatory synapsesthroughout the central nervous system (CNS). These receptors mediate awide range of brain processes, including synaptic plasticity, that areassociated with certain types of memory formation and learning.NMDA-glutamate receptors require binding of two agonists to effectneurotransmission. One of these agonists is the excitatory amino acidL-glutamate, while the second agonist, at the so-called“strychnine-insensitive glycine site”, is now thought to be D-serine. Inanimals, D-serine is synthesized from L-serine by serine racemase anddegraded to its corresponding ketoacid by DAAO. Together, serineracemase and DAAO are thought to play a crucial role in modulating NMDAneurotransmission by regulating CNS concentrations of D-serine.

Alzheimer's disease is manifested as a form of dementia that typicallyinvolves mental deterioration, reflected in memory loss, confusion, anddisorientation. In the context of the present invention, dementia isdefined as a syndrome of progressive decline in multiple domains ofcognitive function, eventually leading to an inability to maintainnormal social and/or occupational performance. Early symptoms includememory lapses and mild but progressive deterioration of specificcognitive functions, such as language (aphasia), motor skills (apraxia)and perception (agnosia). The earliest manifestation of Alzheimer'sdisease is often memory impairment, which is required for a diagnosis ofdementia in both the National Institute of Neurological andCommunicative Disorders and Stroke-Alzheimer's Disease—and theAlzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)criteria (McKhann et al., 1984, Neurology 34:939-944), which arespecific for Alzheimer's disease, and the American PsychiatricAssociation's Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition (DSM-IV) criteria, which are applicable for all forms ofdementia. The cognitive function of a patient may also be assessed bythe Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-cog;Rosen et al., 1984, Am. J. Psychiatry 141:1356-1364). Alzheimer'sdisease is typically treated by acetylcholine esterase inhibitors suchas tacrine hydrochloride or donepezil. Unfortunately, the few forms oftreatment for memory loss and impaired learning available at present arenot considered effective enough to make any significant difference to apatient, and there is currently a lack of a standard nootropic drug foruse in such treatment.

Neuropsychiatric disorders include schizophrenia, autism, and attentiondeficit disorder. Clinicians recognize a distinction among suchdisorders, and there are many schemes for categorizing them. TheDiagnostic and Statistical Manual of Mental Disorders, Revised, FourthEd., (DSM-IV-R), published by the American Psychiatric Association,provides a standard diagnostic system upon which persons of skill rely,and is incorporated herein by reference. According to the framework ofthe DSM-IV, the mental disorders of Axis I include: disorders diagnosedin childhood (such as Attention Deficit Disorder (ADD) and AttentionDeficit—Hyperactivity Disorder (ADHD)) and disorders diagnosed inadulthood. The disorders diagnosed in adulthood include (1)schizophrenia and psychotic disorders; (2) cognitive disorders; (3) mooddisorders; (4) anxiety related disorders; (5) eating disorders; (6)substance related disorders; (7) personality disorders; and (8)“disorders not yet included” in the scheme.

ADD and ADHD are disorders that are most prevalent in children and areassociated with increased motor activity and a decreased attention span.These disorders are commonly treated by administration ofpsychostimulants such as methylphenidate and dextroamphetamine sulfate.

Schizophrenia represents a group of neuropsychiatric disorderscharacterized by dysfunctions of the thinking process, such asdelusions, hallucinations, and extensive withdrawal of the patient'sinterests from other people. Approximately one percent of the worldwidepopulation is afflicted with schizophrenia, and this disorder isaccompanied by high morbidity and mortality rates. So-called negativesymptoms of schizophrenia include affect blunting, anergia, alogia andsocial withdrawal, which can be measured using SANS (Andreasen, 1983,Scales for the Assessment of Negative Symptoms (SANS), Iowa City, Iowa).Positive symptoms of schizophrenia include delusion and hallucination,which can be measured using PANSS (Positive and Negative Syndrome Scale)(Kay et al., 1987, Schizophrenia Bulletin 13:261-276). Cognitivesymptoms of schizophrenia include impairment in obtaining, organizing,and using intellectual knowledge which can be measured by the Positiveand Negative Syndrome Scale-cognitive subscale (PANSS-cognitivesubscale) (Lindenmayer et al., 1994, J. Nerv. Ment. Dis. 182:631-638) orwith cognitive tasks such as the Wisconsin Card Sorting Test.Conventional antipsychotic drugs, which act on the dopamine D₂ receptor,can be used to treat the positive symptoms of schizophrenia, such asdelusion and hallucination. In general, conventional antipsychotic drugsand atypical antipsychotic drugs, which act on the dopamine D₂ and 5HT₂serotonin receptor, are limited in their ability to treat cognitivedeficits and negative symptoms such as affect blunting (i.e., lack offacial expressions), anergia, and social withdrawal.

Other conditions that are manifested as deficits in memory and learninginclude benign forgetfulness and closed head injury. Benignforgetfulness refers to a mild tendency to be unable to retrieve orrecall information that was once registered, learned, and stored inmemory (e.g., an inability to remember where one placed one's keys orparked one's car). Benign forgetfulness typically affects individualsafter 40 years of age and can be recognized by standard assessmentinstruments such as the Wechsler Memory Scale. Closed head injury refersto a clinical condition after head injury or trauma. Such a condition,which is characterized by cognitive and memory impairment, can bediagnosed as “amnestic disorder due to a general medical condition”according to DSM-IV.

Known inhibitors of DAAO include benzoic acid, pyrrole-2-carboxylicacids, and indole-2-carboxylic acids, as described by Frisell, et al.,J. Biol. Chem., 223:75-83 (1956) and Parikh et al., JACS, 80:953 (1958).Indole derivatives and particularly certain indole-2-carboxylates havebeen described in the literature for treatment of neurodegenerativedisease and neurotoxic injury. EP 396124 discloses indole-2-carboxylatesand derivatives for treatment or management of neurotoxic injuryresulting from a CNS disorder or traumatic event or in treatment ormanagement of a neurodegenerative disease. Several examples of traumaticevents that may result in neurotoxic injury are given, includinghypoxia, anoxia, and ischemia, associated with perinatal asphyxia,cardiac arrest or stroke. Neurodegeneration is associated with CNSdisorders such as convulsions and epilepsy. U.S. Pat. Nos. 5,373,018;5,374,649; 5,686,461; 5,962,496 and 6,100,289, to Cugola, disclosetreatment of neurotoxic injury and neurodegenerative disease usingindole derivatives. None of the above references mention improvement orenhancement of learning, memory or cognition.

WO 03/039540 discloses enhancement of learning, memory and cognition andtreatment of neurodegenerative disorders using DAAO inhibitors,including indole-2-carboxylic acids. However, there remains a need fornew drugs that are clinically effective in treating memory defects,impaired learning and loss of cognition, and other symptoms related toNMDA receptor activity, or lack thereof.

Certain pyrazole-3-carboxylic acids are described as partial agonistsfor the nicotinic acid receptor by van Herk, et al. (J. Med. Chem.,46(18):3945-51 (2003)). A synthetic route for preparation of thecompounds is shown, and inhibition of binding of nicotinic acid by thecompounds was determined. There is no mention of activity at the NMDAreceptor, or inhibition of DAAO.

SUMMARY OF THE INVENTION

It has been unexpectedly discovered that certain pyrrole and pyrazolederivatives exhibit more potent inhibition of DAAO activity than knowninhibitors. Dramatically low concentrations of these compounds have beenobserved to inhibit DAAO in vitro, particularly relative to known DAAOinhibitors such as benzoic acid, pyrrole-2-carboxylic acid, andindole-2-carboxylic acid. Because of this ability to inhibit DAAOactivity, the certain pyrrole and pyrazole derivatives are useful intreating a variety of diseases and/or conditions wherein modulation ofD-Serine levels, and/or its oxidative products, is effective inameliorating symptoms, along with a reduction in undesirable sideeffects. In particular, the compounds may be useful for increasingD-Serine levels and reducing levels of toxic products of D-Serineoxidation; thus, the compounds are useful for enhancing learning, memoryand/or cognition, or for treating schizophrenia, for treating orpreventing loss of memory and/or cognition associated with Alzheimer'sdisease, for treating ataxia, or for preventing loss of neuronalfunction characteristic of neurodegenerative diseases.

Accordingly, in one aspect, the invention relates to methods forincreasing D-Serine and reducing the toxic products of D-Serineoxidation, for enhancing learning, memory and/or cognition, or fortreating schizophrenia, for treating or preventing loss of memory and/orcognition associated with Alzheimer's disease, for treating ataxia, fortreating neuropathic pain, or for preventing loss of neuronal functioncharacteristic of neurodegenerative diseases.

The methods involve administering to a subject a therapeutic amount of acompound of formula I, or a pharmaceutically acceptable salt or solvatethereof:

wherein

-   -   R¹ and R² are independently selected from hydrogen, halo, nitro,        alkyl, acyl, alkylaryl, and XYR⁵;    -   or R¹ and R², taken together, form a 5, 6, 7 or 8-membered        substituted or unsubstituted carbocyclic or heterocyclic group;    -   X and Y are independently selected from O, S, NH, and        (CR⁶R⁷)_(n);    -   R³ is hydrogen, alkyl or M⁺;    -   M is aluminum, calcium, lithium, magnesium, potassium, sodium,        zinc or a mixture thereof;    -   R⁶ and R⁷ are independently selected from hydrogen and alkyl;    -   Z is N or CR⁴;    -   R⁴ is from selected from hydrogen, halo, nitro, alkyl,        alkylaryl, and XYR⁵;    -   R⁵ is selected from aryl, substituted aryl, heteroaryl and        substituted heteroaryl;    -   n is an integer from 1 to 6;    -   at least one of R¹, R² and R⁴ is other than hydrogen; and    -   at least one of X and Y is (CR⁶R⁷)_(n).

In a second aspect the invention relates to methods for treating autism,schizophrenia, Alzheimer's disease, ataxia, neuropathic pain orneurodegenerative diseases, comprising administering a therapeuticallyeffective amount of the above D-amino acid oxidase (DAAO) inhibitor offormula I to a subject in need of treatment for one or more of theseconditions.

In preferred embodiments, the compounds of formula I are substitutedpyrrole-2-carboxylic acids or pyrazole-3-carboxylic acids, for example:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods for increasing D-serine andreducing the toxic products of D-serine oxidation, for enhancinglearning, memory and/or cognition, or for treating schizophrenia, fortreating or preventing loss of memory and/or cognition associated withAlzheimer's disease, for treating ataxia, or for preventing loss ofneuronal function characteristic of neurodegenerative diseases. Themethods include administering to a subject a therapeutic amount of acompound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   -   R¹ and R² are independently selected from hydrogen, halo, nitro,        alkyl, acyl, alkylaryl, and XYR⁵;    -   or R¹ and R², taken together, form a 5, 6, 7 or 8-membered        substituted or unsubstituted carbocyclic or heterocyclic group;    -   X and Y are independently selected from O, S, NH, and        (CR⁶R⁷)_(n);    -   R³ is hydrogen, alkyl or M⁺;    -   M is aluminum, calcium, lithium, magnesium, potassium, sodium,        zinc or a mixture thereof;    -   R⁶ and R⁷ are independently selected from hydrogen and alkyl;    -   Z is N or CR⁴;    -   R⁴ is from selected from hydrogen, halo, nitro, alkyl,        alkylaryl, and XYR⁵;    -   R⁵ is selected from aryl, substituted aryl, heteroaryl and        substituted heteroaryl;    -   n is an integer from 1 to 6;    -   at least one of R¹, R² and R⁴ is other than hydrogen; and    -   at least one of X and Y is (CR⁶R⁷)_(n).

Therapeutic treatment with a compound of formula I improves and/orenhances memory, learning and cognition, particularly in individualssuffering from neurodegenerative diseases such as Alzheimer's,Huntington's or Parkinson's diseases. The compounds also amelioratecognitive dysfunctions associated with aging and improve catatonicschizophrenia.

Compounds of formula I possess unique pharmacological characteristicswith respect to inhibition of DAAO, and influence the activity of theNMDA receptor in the brain, particularly by controlling the levels ofD-serine. Therefore, these compounds are effective in treatingconditions and disorders, especially CNS-related disorders, modulated byDAAO, D-serine and/or NMDA receptor activity, with diminished sideeffects compared to administration of the current standards oftreatment. These conditions and disorders include, but are not limitedto, neuropsychiatric disorders, such as schizophrenia, autism, attentiondeficit disorder (ADD and ADHD) and childhood learning disorders, andneurodegenerative diseases and disorders, such as MLS (cerebellarataxia), Alzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, Down syndrome, neuropathic pain,multi-infarct dementia, status epilecticus, contusive injuries (e.g.spinal cord injury and head injury), viral infection inducedneurodegeneration, (e.g. AIDS, encephalopathies), epilepsy, benignforgetfulness, and closed head injury. Compounds of formula I may alsobe useful for the treatment of neurotoxic injury that follows cerebralstroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia,cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatalasphyxia and cardiac arrest.

Accordingly, the present invention relates to methods for increasing theconcentration of D-serine and/or decreasing the concentration of toxicproducts of D-serine oxidation by DAAO in a mammal, for treatingschizophrenia, for treating or preventing loss of memory and/orcognition associated with Alzheimer's disease, for treating ataxia, orfor preventing loss of neuronal function characteristic ofneurodegenerative diseases, for enhancing learning, memory and/orcognition, or for treating neuropathic pain. Each of the methodscomprises administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof:

wherein

-   -   R¹ and R² are independently selected from hydrogen, halo, nitro,        alkyl, acyl, alkylaryl, arylalkyl, and XYR⁵; or R¹ and R², taken        together, form a 5, 6, 7 or 8-membered substituted or        unsubstituted carbocyclic or heterocyclic group;    -   X and Y are independently selected from O, S, NH, and        (CR⁶R⁷)_(n);    -   R³ is hydrogen, alkyl or M⁺;    -   M is aluminum, calcium, lithium, magnesium, potassium, sodium,        zinc or a mixture thereof;    -   Z is N or CR⁴;    -   R⁴ is from selected from hydrogen, halo, nitro, alkyl,        alkylaryl, arylalkyl and XYR⁵;    -   R⁵ is selected from aryl, substituted aryl, heteroaryl and        substituted heteroaryl;    -   R⁶ and R⁷ are independently selected from hydrogen and alkyl;    -   n is an integer from 1 to 6;    -   at least one of R¹, R² and R⁴ is other than hydrogen; and    -   at least one of X and Y is (CR⁶R⁷)_(n).

In some embodiments, D-serine or cycloserine may be coadministered alongwith the compound(s) of formula I.

Compounds of formula I are typically more selective than known DAAOinhibitors, including indole-2-carboxylates, and demonstrate higherselectivity for DAAO inhibition relative to binding at the NMDAreceptor's D-serine binding site. The compounds also exhibit anadvantageous profile of activity including good bioavailability.Accordingly, they offer advantages over many art-known methods fortreating disorders modulated by DAAO, D-serine or NMDA receptoractivity. For example, unlike many conventional antipsychotictherapeutics, DAAO inhibitors can produce a desirable reduction in thecognitive symptoms of schizophrenia. Conventional antipsychotics oftenproduce undesirable side effects, including tardive dyskinesia(irreversible involuntary movement disorder), extra pyramidal symptoms,and akathesia, and these may be reduced or eliminated by administeringcompounds of formula I.

In another aspect, the present invention also relates to compounds offormula IA, or pharmaceutically acceptable salts or solvates thereof,and pharmaceutical compositions containing them:

wherein

-   -   R^(1a), R^(2a) and R⁴ are independently selected from hydrogen,        halo, nitro, alkyl, arylalkyl, alkylaryl, and XYR⁵;    -   X and Y are independently selected from O, S, NH, and        (CR⁶R⁷)_(n);    -   R³ is hydrogen, alkyl or M⁺;    -   M is aluminum, calcium, lithium, magnesium, potassium, sodium,        zinc or a mixture thereof;    -   R⁵ is selected from aryl, substituted aryl, heteroaryl and        substituted heteroaryl;    -   R⁶ and R⁷ are independently selected from hydrogen and alkyl;    -   Z is N or CR⁴;    -   n is an integer from 1 to 6;    -   at least one of R^(1a) and R^(2a) is XYR⁵; and    -   at least one of X and Y is (CR⁶R⁷)_(n);    -   with the proviso that formula 1A does not include        5-phenethyl-1H-pyrazole-3-carboxylic acid, that is, when R^(1a)        is hydrogen, R^(2a) is XYR⁵; X and Y are (CR⁶R⁷)_(n); R³ is        hydrogen, R⁶ and R⁷ are hydrogen; Z is N; n is 2, R⁵ may not be        phenyl.

Compounds of formula IA form a subset of the compounds of formula I, andmay therefore be used in the methods of the present invention withoutlimitation.

In preferred embodiments, the compounds of formula I and IA arepyrrole-2-carboxylic acids, substituted at the 4-position, orpyrazole-3-carboxylic acids, substituted at the 5-position. Preferredsubstituents for compounds of formula I and IA, 4-substitutedpyrrole-2-carboxylic acids and 5-substituted pyrazole-3-carboxylic acidsare arylalkyl, substituted arylalkyl, and higher alkyl (C₆C₂₀).Preferred arylalkyl substituents are arylethyl groups, particularlyphenethyl, in such embodiments, the compounds of formula I and IA arepyrrole-2-carboxylic acids, substituted at the 4-position with asubstituted or unsubstituted aryl group joined to the 4-position of thepyrrole through a two-atom tether, or a pyrazole-3-carboxylic acid,substituted at the 5-position with a substituted or unsubstituted arylgroup joined to the 5-position of the pyrrole through a two-atom tether.In other preferred embodiments of the compounds of formula I and IA,pyrrole-2-carboxylic acids and pyrazole-3-carboxylic acids, R¹ and R²,taken together, form a 5, 6, 7 or 8-membered substituted orunsubstituted carbocyclic or heterocyclic group.

Particularly preferred pyrrole and pyrazole D-amino acid oxidaseinhibitors include:

The invention includes compounds of formula I and IA, as well aspharmaceutically acceptable salts and solvates of these compounds. Theterminology “compound or a pharmaceutically acceptable salt or solvateof a compound” intends the inclusive meaning of “or”, in that a materialthat is both a salt and a solvate is encompassed. Pharmaceuticallyacceptable salts include, but are not limited to, inorganic salts ofaluminum, calcium, lithium, magnesium, potassium, sodium and zinc, andorganic salts of lysine, N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine),procaine and tromethamine.

The compounds of formula I and IA may be prepared by known methods, bythe procedures illustrated in the Examples, or by the methods shown inSchemes 1-5.

Subjects for treatment according to the present invention include humans(patients) and other mammals in need of therapy for the statedcondition. Patients having a need for therapy for improving or enhancinglearning and memory are those exhibiting symptoms of dementia orlearning and memory loss. Individuals with an amnesic disorder areimpaired in their ability to learn new information or are unable torecall previously learned information or past events. The memory deficitis most apparent on tasks to require spontaneous recall and may also beevident when the examiner provides stimuli for the person to recall at alater time. The memory disturbance must be sufficiently severe to causemarked impairment in social or occupational functioning and mustrepresent a significant decline from a previous level of functioning.The memory deficit may be age-related or the result of disease or othercause. Dementia is characterized by multiple clinically significantdeficits in cognition that represent a significant change from aprevious level of functioning, including memory impairment involvinginability to learn new material or forgetting of previously learnedmaterial. Memory can be formally tested by measuring the ability toregister, retain, recall and recognize information. A diagnosis ofdementia also requires at least one of the following cognitivedisturbances: aphasia, apraxia, agnosia or a disturbance in executivefunctioning. These deficits in language, motor performance, objectrecognition and abstract thinking, respectively, must be sufficientlysevere in conjunction with the memory deficit to cause impairment inoccupational or social functioning and must represent a decline from apreviously higher level of functioning.

Compounds of formula I and IA may also be used in conjunction withtherapy involving administration of D-serine or an analog thereof, suchas a salt of D-serine, an ester of D-serine, alkylated D-serine, or aprecursor of D-serine, or can be used in conjunction with therapyinvolving administration of antipsychotics, antidepressants,psychostimulants, and/or Alzheimer's disease therapeutics.

In animals, several established models of learning and memory areavailable to examine the beneficial cognitive enhancing effects andpotential related side effects of treatment. Descriptions of tests thatmay be employed to assess changes in cognition in non-human species aregiven in Sarter, Martin, Intern. J. Neuroscience, 32:765-774 (1987). Thetests include the Morris water maze (Stewart and Morris, BehavioralNeuroscience, R. Saghal, Ed., p. 107 (1993)), delayed non-match tosample and social discrimination models.

The Morris water maze is one of the best-validated models of learningand memory, and it is sensitive to the cognitive enhancing effects of avariety of pharmacological agents. The task performed in the maze isparticularly sensitive to manipulations of the hippocampus in the brain,an area of the brain important for spatial learning in animals andmemory consolidation in humans. Moreover, improvement in Morris watermaze performance is predictive of clinical efficacy of a compound as acognitive enhancer. For example, treatment with cholinesteraseinhibitors or selective muscarinic cholinergic agonists reverse learningdeficits in the Morris maze animal model of learning and memory, as wellas in clinical populations with dementia. In addition, this animalparadigm accurately models the increasing degree of impairment withadvancing age and the increased vulnerability of the memory trace topre-test delay or interference which is characteristic of amnesiacpatients. The test is a simple spatial learning task in which the animalis placed in a tank of tepid water, which is opaque due to the additionof powdered milk. The animals learn the location of the platformrelative to visual cues located within the maze and the testing room;this learning is referred to as place learning. Groups of animalsreceive control solution or a dosage of the therapeutic agent, at thedesired time interval prior to training or after training. Controlanimals typically reach the platform within five to ten seconds afterthree days of training. The measure of the memory modulator effects of atherapeutic agent is a shift of this time period. In the second or probephase of the test, animals which have previously learned the position ofthe platform are placed in the tank from which the platform has beenremoved. Animals that remember the position of the platform will spendmore time in the quadrant that had contained the platform and will makemore crossings over the position previously occupied by the platform.Increases in memory or cognitive ability are manifested by animalsspending more time in the correct quadrant or making more crossing overthe position previously occupied by the platform as compared withcontrol animals. Decreases in memory or cognitive ability are manifestedby animals spending less time in the correct quadrant or making lesscrossings of the platform position than control animals.

In the delayed non-match to sample test an animal is presented with astimulus (for example lever A). After a period of time the animal ispresented with two choices (example lever A and lever B). Selection ofthe choice that does not match the original stimulus (lever B) resultsin a reward. Greater than chance selection of the proper choiceindicates that the original stimulus was remembered. As the time betweenstimulus and choice response is increased, performance decreases andapproaches pure chance. The number of correct choices at a given time isrelated to cognitive ability. Deficits in cognition or memory may beinduced physically, biochemically or by the use of aged animals.

In the social interaction test a foreign animal (animal B) is introducedinto the home cage of the test animal (animal A). Animal A willrecognize the introduced animal as foreign and investigate it. If animalB is removed and reintroduced at a later time, the test animal (animalA) will spend less time investigating the new cage mate as it remembersit from the previous introduction. As time between introductionsincreases, more time is spent investigating the new animal the secondtime as it is less well remembered. The time spent investigating the newcage mate during the second introduction is inversely related tocognitive ability. Deficits in cognition or memory may be introducedphysically, biochemically or by the use of aged animals.

In humans, methods for improving learning and memory may be measured bysuch tests as the Wechsler Memory Scale and the Minimental test. Astandard clinical test for determining if a patient has impairedlearning and memory is the Minimental Test for Learning and Memory(Folstein et al., J. Psychiatric Res. 12:185, 1975), especially forthose suffering from head trauma, Korsakoff's disease or stroke. Thetest result serves as an index of short-term, working memory of the kindthat deteriorates rapidly in the early stages of dementing or amnesiacdisorders. Ten pairs of unrelated words (e.g., army-table) are read tothe subject. Subjects are then asked to recall the second word whengiven the first word of each pair. The measure of memory impairment is areduced number of paired-associate words recalled relative to a matchedcontrol group. Improvement in learning and memory constitutes either (a)a statistically significant difference between the performance oftreated patients as compared to members of a placebo group; or (b) astatistically significant change in performance in the direction ofnormality on measures pertinent to the disease model. Animal models orclinical instances of disease exhibit symptoms which are by definitiondistinguishable from normal controls. Thus, the measure of effectivepharmacotherapy will be a significant, but not necessarily complete,reversal of symptoms. Improvement can be facilitated in both animal andhuman models of memory pathology by clinically effective “cognitiveenhancing” drugs which serve to improve performance of a memory task.For example, cognitive enhancers which function as cholinomimeticreplacement therapies in patients suffering from dementia and memoryloss of the Alzheimer's type significantly improve short-term workingmemory in such paradigms as the paired-associate task. Another potentialapplication for therapeutic interventions against memory impairment issuggested by age-related deficits in performance which are effectivelymodeled by the longitudinal study of recent memory in aging mice.

The Wechsler Memory Scale is a widely used pencil-and-paper test ofcognitive function and memory capacity. In the normal population, thestandardized test yields a mean of 100 and a standard deviation of 15,so that a mild amnesia can be detected with a 10-15 point reduction inthe score, a more severe amnesia with a 20-30 point reduction, and soforth. During the clinical interview, a battery of tests, including, butnot limited to, the Minimental test, the Wechsler memory scale, orpaired-associate learning are applied to diagnose symptomatic memoryloss. These tests provide general sensitivity to both general cognitiveimpairment and specific loss of learning/memory capacity (Squire, 1987).Apart from the specific diagnosis of dementia or amnestic disorders,these clinical instruments also identify age-related cognitive declinewhich reflects an objective diminution in mental function consequent tothe aging process that is within normal limits given the person's age(DSM IV, 1994). As noted above, “improvement” in learning and memorywithin the context of the present invention occurs when there is astatistically significant difference in the direction of normality inthe paired-associate test, for example, between the performance oftherapeutic agent treated patients as compared to members of the placebogroup or between subsequent tests given to the same patient.

The prepulse inhibition test may be used to identify compounds that areeffective in treating schizophrenia. The test is based upon theobservations that animals or humans that are exposed to a loud soundwill display a startle reflex and that animals or humans exposed to aseries of lower intensity sounds prior to the higher intensity testsound will no longer display as intense of a startle reflex. This istermed prepulse inhibition. Patients diagnosed with schizophreniadisplay defects in prepulse inhibition, that is, the lower intensityprepulses no longer inhibit the startle reflex to the intense testsound. Similar defects in prepulse inhibition can be induced in animalsvia drug treatments (scopolamine, ketamine, PCP or MK801) or by rearingoffspring in isolation. These defects in prepulse inhibition in animalscan be partially reversed by drugs known to be efficacious inschizophrenia patients. It is felt that animal prepulse inhibitionmodels have face value for predicting efficacy of compounds in treatingschizophrenia patients.

If desired, compounds of formula I and IA may also be used inconjunction with therapy involving administration of D-serine or ananalog thereof, such as a salt of D-serine, an ester of D-serine,alkylated D-serine, or a precursor of D-serine. The compounds may alsobe used in conjunction with therapy involving administration ofantipsychotics (for treating schizophrenia and other psychoticconditions), psychostimulants (for treating attention deficit disorder,depression, or learning disorders), antidepressants, nootropics (forexample, piracetam, oxiracetam or aniracetam), acetylcholinesteraseinhibitors (for example, the physostigmine related compounds, tacrine ordonepezil) and/or Alzheimer's disease therapeutics (for treatingAlzheimer's disease). Such methods for conjoint therapies are includedwithin the invention.

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect by inhibition of DAAO in at least a sub-population ofcells in an animal and thereby blocking the biological consequences ofthat pathway in the treated cells, at a reasonable benefit/risk ratioapplicable to any medical treatment.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases including inorganicbases and organic bases. Suitable pharmaceutically acceptable baseaddition salts for the compounds of the present invention includemetallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylene diamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), procaine andtromethamine.

In general, the compounds of the present invention are commerciallyavailable or may be prepared by methods well known to persons of skillin the art. In addition, methods described below, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures may be employed. In these reactions,it is also possible to make use of variants that are in themselvesknown, but are not mentioned here.

In the context of the present invention, alkyl is intended to includelinear, branched, or cyclic hydrocarbon structures and combinationsthereof, including lower alkyl and higher alkyl. Preferred alkyl groupsare those of C₂₀ or below. Lower alkyl refers to alkyl groups of from 1to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and includesmethyl, ethyl, n-propyl, isopropyl, and n-, s- and t-butyl. Higher alkylrefers to alkyl groups having seven or more carbon atoms, preferably7-20 carbon atoms, and includes, for example, n-, s- and t-heptyl,octyl, and dodecyl. Cycloalkyl is a subset of alkyl and includes cyclichydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, and norbornyl.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from nitrogen, oxygen orsulfur; a bicyclic 9- or 10-membered aromatic or heteroaromatic ringsystem containing 0-3 heteroatoms selected from nitrogen, oxygen orsulfur; or a tricyclic 13- or 14-membered aromatic or heteroaromaticring system containing 0-3 heteroatoms selected from nitrogen, oxygen orsulfur. The aromatic 6- to 14-membered carbocyclic rings include, forexample, benzene, naphthalene, indane, tetralin, and fluorene; and the5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole,pyridine, indole, thiophene, benzopyranone, thiazole, pyrrole, furan,benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

Arylalkyl means an alkyl residue attached to an aryl ring. Examples arebenzyl and phenethyl. Heteroarylalkyl means an alkyl residue attached toa heteroaryl ring. Examples include pyridinylmethyl andpyrimidinylethyl. Alkylaryl means an aryl residue having one or morealkyl groups attached thereto. Examples are tolyl and mesityl.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.Lower alkoxy refers to groups containing one to four carbons.

Acyl refers to groups of from 1 to 20 carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, andbenzyloxycarbonyl. Lower-acyl refers to groups containing one to fourcarbons.

Heterocycle or heterocyclic means a cycloalkyl or aryl residue in whichone to two of the carbons is replaced by a heteroatom such as oxygen,nitrogen or sulfur. Examples of heterocycles that fall within the scopeof the invention include pyrrolidine, pyrazole, pyrrole, indole,quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran,benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl,when occurring as a substituent), tetrazole, morpholine, thiazole,pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline,isoxazole, dioxane, and tetrahydrofuran.

Substituted refers to residues, including, but not limited to, alkyl,alkylaryl, aryl, arylalkyl, and heteroaryl, wherein up to three H atomsof the residue are replaced with lower alkyl, substituted alkyl,substituted alkynyl, haloalkyl, alkoxy, carbonyl, carboxy, carboxalkoxy,carboxamido, acyloxy, amidino, nitro, halogen, hydroxy, OCH(COOH)₂,cyano, primary amino, secondary amino, acylamino, alkylthio, sulfoxide,sulfone, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, orheteroaryloxy.

Haloalkyl refers to an alkyl residue, wherein one or more H atoms arereplaced by halogen atoms; the term haloalkyl includes perhaloalkyl.Examples of haloalkyl groups that fall within the scope of the inventioninclude CH₂F, CHF₂, and CF₃.

Oxaalkyl refers to an alkyl residue in which one or more carbons havebeen replaced by oxygen. It is attached to the parent structure throughan alkyl residue. Examples include methoxypropoxy, 3,6,9-trioxadecyl andthe like. The term oxaalkyl is intended as it is understood in the art[see Naming and Indexing of Chemical Substances for Chemical Abstracts,published by the American Chemical Society, ¶196, but without therestriction of ¶127(a)], i.e. it refers to compounds in which the oxygenis bonded via a single bond to its adjacent atoms (forming ether bonds);it does not refer to doubly bonded oxygen, as would be found in carbonylgroups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues inwhich one or more carbons has been replaced by sulfur or nitrogen,respectively. Examples include ethylaminoethyl and methylthiopropyl.

In the context of the present invention, compounds that are consideredto possess activity as DAAO inhibitors are those displaying 50%inhibition of the enzymatic cycle of DAAO (IC₅₀) a concentration ofabout ≦100 μM, preferably, about ≦10 μM and more preferably about ≦1 μM.

Many of the compounds described herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—. The present invention is meant toinclude all such possible isomers, as well as, their racemic andoptically pure forms. Optically active (R)— and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

While it may be possible for compounds of formula I and IA to beadministered as the raw chemical, it is preferable to present them as apharmaceutical composition. According to a further aspect, the presentinvention provides a pharmaceutical composition comprising a compound offormula I or IA or a pharmaceutically acceptable salt or solvatethereof, together with one or more pharmaceutically carriers thereof andoptionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration. The most suitable route maydepend upon the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing into association a compound or apharmaceutically acceptable salt or solvate thereof (“activeingredient”) with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation. Oralformulations, are well known to those skilled in the art, and generalmethods for preparing them are found in any standard pharmacy schooltextbook, for example, Remington: The Science and Practice of Pharmacy.,A. R. Gennaro, ed. (1995), the entire disclosure of which isincorporated herein by reference.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed or controlled releaseof the active ingredient therein. Oral and parenteral sustained releasedrug delivery systems are well known to those skilled in the art, andgeneral methods of achieving sustained release of orally or parenterallyadministered drugs are found, for example, in Remington: The Science andPractice of Pharmacy, pages 1660-1675 (1995).

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient. Formulations for parenteraladministration also include aqueous and non-aqueous sterile suspensions,which may include suspending agents and thickening agents. Theformulations may be presented in unit-dose of multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of a sterile liquidcarrier, for example saline, phosphate-buffered saline (PBS) or thelike, immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described. Formulations for rectal administrationmay be presented as a suppository with the usual carriers such as cocoabutter or polyethylene glycol. Formulations for topical administrationin the mouth, for example, buccally or sublingually, include lozengescomprising the active ingredient in a flavored basis such as sucrose andacacia or tragacanth, and pastilles comprising the active ingredient ina basis such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions containing compounds of formula I or IA maybe conveniently presented in unit dosage form and prepared by any of themethods well known in the art of pharmacy. Preferred unit dosageformulations are those containing an effective dose, or an appropriatefraction thereof, of the active ingredient, or a pharmaceuticallyacceptable salt thereof. The magnitude of a prophylactic or therapeuticdose typically varies with the nature and severity of the condition tobe treated and the route of administration. The dose, and perhaps thedose frequency, will also vary according to the age, body weight andresponse of the individual patient. In general, the total daily doseranges from about 1 mg per day to about 7000 mg per day, preferablyabout 1 mg per day to about 100 mg per day, and more preferably, about25 mg per day to about 50 mg per day, in single or divided doses. Insome embodiments, the total daily dose may range from about 50 mg toabout 500 mg per day, and preferably, about 100 mg to about 500 mg perday. It is further recommended that children, patients over 65 yearsold, and those with impaired renal or hepatic function, initiallyreceive low doses and that the dosage be titrated based on individualresponses and blood levels. It may be necessary to use dosages outsidethese ranges in some cases, as will be apparent to those in the art.Further, it is noted that the clinician or treating physician knows howand when to interrupt, adjust or terminate therapy in conjunction withindividual patient's response.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

EXAMPLES Procedures for the Preparation of Pyrazoles Example 1 Synthesisof 6,6-Dimethyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid(3)

Synthesis of (3,3-Dimethyl-2-oxocyclopentl)-oxoacetic acid ethyl ester(1)

Sodium hydride (0.428 g, 17.8 mmol) was added slowly to a NaCl ice bathcontaining EtOH (5.4 mL, 3.3 M) stirring under N₂.2,2-dimethylcyclopentanone (2.00 g, 17.83 mmol) and diethyloxalate (2.42mL, 17.8 mmol) were mixed together, and then added to the chilled NaOEtsolution. After stirring for 15 minutes, the reaction was warmed to roomtemperature and stirred for 6 hours, at which point the reaction wasjudged complete by TLC. The reaction was quenched at 0° C. with 1N HCland extracted 2× with CH₂Cl₂. The combined organics were washed withH₂O, dried with Na₂SO₄, filtered, and concentrated to yield 3.4084 g(90.0%) of crude 2 that was sufficiently pure by NMR to go on to thenext step without further purification. Note: NaOEt purchased fromAldrich may be substituted for the NaOEt synthesized in situ. ¹H (CDCl₃,400 MHz): δ 4.29 (2H, q, J=7.3 Hz), 2.82 (2H, t, J=7.3 Hz), 1.76 (2H, t,J=7.3 Hz), 1.32 (3H, t, J=7.3 Hz), 1.07 (6H, s) ppm. ¹³C (CDCl₃, 100MHz): δ 218, 162.89, 153.15, 115.98, 62.12, 46.16, 36.39, 23.98, 23.87,14.22 ppm.

Synthesis of6,6-dimethyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acidethyl ester (2)

Hydrazine hydrate (0.229 mL, 4.71 mmol) was added to a stirring roomtemperature solution of 1 (0.9961 g, 4.71 mmol) in EtOH (4.7 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby TLC (2 h). The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 70:30:2 Hexanes:CH₂Cl₂:2N NH₃ inEtOH). Only pure fractions were combined and concentrated to obtain0.6955 g (71.2%) of 2. ¹H (CDCl₃, 400 MHz): δ 11.04 (1H, broad s), 4.33(2H, q, J=7.3 Hz), 2.76 (2H, t, J=6.8 Hz), 2.26 (2H, t, J=6.8 Hz), 1.33(3H, t, J=7.3 Hz), 1.31 (6H, s) ppm. ¹³C (CDCl₃, 100 MHz): δ 168.08,160.61, 128.73, 127.27, 61.15, 47.22, 38.64, 27.57, 22.00, 14.48 ppm.

Synthesis of6,6-Dimethyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid (3)

Freshly prepared aq. NaOH (10 M in H₂O, 15.1 mmol) was added to astirring, room temperature solution of 2 (0.6289 g, 3.02 mmol) in MeOH(7.6 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by TLC (2.5 h). The reaction wasconcentrated, redissolved in EtOAc and H₂O, and extracted with EtOAc.10% aq. HCl was added dropwise until the pH=4, then the organic wasremoved, and the aqueous layer was extracted with EtOAc again. Thecombined organics were dried with Na₂SO₄, filtered, and concentrated. Asmall amount of CH₂Cl₂ and hexanes were added to the colored solidproduct, and the colored impurity was pipetted off. The remaining solidwas dried to obtain 0.2371 g (43.6%) of 3 as an off-white solid. Note:The precipitation method used below appears to be the preferredprotocol. ¹H (CD₃OD, 400 MHz): δ 2.75 (2H, t, J=6.8 Hz), 2.29 (2H, t,J=6.8 Hz), 1.29 (6H, s) ppm. ¹³C (CD₃OD, 100 MHz): δ 166.15, 162.23,130.46, 126.93, 47.10, 38.22, 26.62, 21.52 ppm. DEPT (CD₃OD, 100 MHz):CH₃ carbons: 26.62; CH₂ carbons: 47.10, 21.52 ppm: LCMS: 181.4 (M+1);163.6 ((M+1)-18). HPLC: 7.538 min.

Example 2 Synthesis of3-methyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid (6)

Synthesis of (3-methyl-2-oxocyclopentyl)-oxoacetic acid ethyl ester (4)

2-methylcyclopentanone (1.0058 g, 10.2 mmol) and diethyloxalate (1.38mL, 10.2 mmol) were mixed together, and then added to a solution ofNaOEt (˜3 M, 3.4 mL) stirring in an ice bath under N₂. After stirringfor 15 minutes, the reaction was warmed to room temperature and stirredovernight. The reaction was quenched at 0° C. with 1N HCl and extracted2× with CH₂Cl₂. The combined organics were washed with H₂O, dried withNa₂SO₄, filtered, and concentrated to yield crude 4. The crude materialwas purified with 98:2 to 96:4 Hexanes:EtOAc to obtain 0.5635 g (27.7%)of 4. ¹H (CDCl₃, 400 MHz): δ 4.29 (2H, q, J=7.1 Hz), 2.96 (1H, ddd,J=17.6, 8.1, 1.5 Hz), 2.69 (1H, ddd, J=17.6, 9.5, 8.1 Hz), 2.57-2.47(1H, m), 2.24 (1H, dtd, J=12.5, 8.3, 2.4 Hz), 1.49 (1H, dtd, J=12.5,10.3, 8.4 Hz), 1.34 (3H, t, J=7.1 Hz), 1.13 (3H, d, J=7.0 Hz) ppm. ¹³C(CDCl₃, 100 MHz): δ 164.09, 153.19, 117.67, 62.92, 30.60, 30.36, 26.55,14.63, 14.37 ppm.

Synthesis 6-methyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylicacid ethyl ester (5)

Hydrazine hydrate (0.101 mL, 2.05 mmol) was added to a stirring roomtemperature solution of 4 (0.4055 g, 2.05 mmol) in EtOH (2.0 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby TLC. The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 96:4 Hexanes:2N NH₃ in EtOH): Onlypure fractions were combined and concentrated to obtain 0.2003 g (50.4%)of 5. ¹H (CDCl₃, 400 MHz): δ 9.55 (1H, broad s), 4.35 (2H, q, J=7.1 Hz),3.26-3.16 (1H, m), 2.89-2.63 (3H, m), 2.09-1.98 (1H, m), 1.37 (3H, t,J=7.2 Hz), 1.30 (3H, d, J=6.9 Hz) ppm. Partial ¹³C (CDCl₃, 100 MHz): δ128.67, 61.32, 39.73, 32.64, 22.94, 19.62, 14.52 ppm. HPLC: 8.901 min.

Synthesis of 6-methyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylicacid (6)

Freshly prepared aq. NaOH (10 M in H₂O, 5.02 mmol) was added to astirring, room temperature solution of 5 (0.1949 g, 1.00 mmol) in MeOH(12.5 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by TLC (0.5 h). The reaction wasconcentrated and then dissolved in 2 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 0.1223 g (73.3%) of 6. ¹H (CD₃OD, 400MHz): δ 3.18-3.07 (1H, m), 2.84-2.62 (3H, m), 2.08-1.96 (1H, m), 1.25(3H, d, J=6.8 Hz) ppm. ¹³C (CD₃OD, δ 164.49, 163.43, 131.67, 129.41,40.87, 33.40, 23.61, 19.73 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons:19.73; CH₂ carbons: 40.87, 23.61; CH carbons: 33.40 ppm. HPLC: 7.006min.

Example 3 Synthesis of4-methyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid (11) and5-methyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylic acid (12)

Synthesis of (2-methyl-5-oxocyclopentyl)-oxoacetic acid ethyl ester (7)and (4-methyl-2-oxocyclopentyl)-oxoacetic acid ethyl ester (8)

Sodium hydride (0.122 g, 5.09 mmol) was added slowly to a NaCl ice bathcontaining EtOH (1.54 mL, 3.3 M) stirring under N₂.3-methylcyclopentanone (0.500 g, 5.09 mmol) and diethyloxalate (0.69 mL,5.09 mmol) were mixed together, and then added to the chilled NaOEtsolution. After stirring for 15 minutes, the reaction was warmed to roomtemperature and stirred for 6 hours, at which point the reaction wasjudged complete by TLC. The reaction was quenched at 0° C. with 1N HCland extracted 2× with CH₂Cl₂. The combined organics were washed withH₂O, dried with Na₂SO₄, filtered, and concentrated to yield 0.5591 g(55.4%) of crude 7 and 8 as an approximately 1:1.1 mixture. Althoughconditions to separate the isomers were not found, the mixture wassufficiently pure by NMR to go on to the next step without furtherpurification. Note: NaOEt purchased from Aldrich may be substituted forthe NaOEt synthesized in situ. ¹H (CDCl₃, 400 MHz): δ 4.33 & 4.31 (2H,q, J=7.3 Hz, 3.54-3.45, 3.20-3.08, 2.64-2.30, 2.15-2.04, 1.74-1.66, 1.35& 1.34 (3H, t, J=7.3 Hz, 1.16 & 1.10 (3H, d, J=7.3 & 6.4 Hz) ppm. ¹³C(CDCl₃, 100 MHz): δ 214.05, 162.98, 152.36, 117.34, 62.23, 46.44, 35.92& 35.76, 29.45 & 28.65, 21.00 & 20.91, 14.25 & 14.17 ppm.

Synthesis of 4-methyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylicacid (9) and 5-methyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylicacid ethyl ester (10)

Hydrazine hydrate (0.127 mL, 2.62 mmol) was added to a stirring roomtemperature solution of 7 and 8 (0.5064 g, 2.62 mmol) in EtOH (2.6 mL, 1M) under N₂. The reaction was then heated to reflux until judgedcomplete by TLC (2.3 h). The reaction was concentrated and purified bysilica gel chromatography (Combiflash column, 70:30:2 Hexanes:CH₂Cl₂:2NNH₃ in EtOH). Only pure fractions were combined and concentrated toobtain 0.3132 g (63.1%) of 9 and 10. Conditions to separate the isomerswere not found. ¹H (CDCl₃, 400 MHz): δ 11.26 & 11.18 (1H, broad s), 4.35& 4.34 (2H, q, J=7.3 Hz), 3.28-3.18 (0.48H, m), 3.02-2.90 (1.5H, m),2.86-2.76 (0.52H, m), 2.74-2.61 (1H, m), 2.09-1.88 (1H, m), 2.15-1.80(0.52H, m), 1.36 & 1.35 (3H, t, J=7.3 Hz), 1.28 & 1.19 (3H, d, J=6.3 Hzfor 1.28 & 4.4 Hz for 1.19) ppm. Partial ¹³C (CDCl₃, 100 MHz): δ 133.67,128.61, 61.12, 40.25 & 39.35, 33.24 & 32.46, 32.30 & 23.91, 21.69 &20.55, 14.48 & 14.46 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 21.69 &20.55, 14.48 & 14.46; CH₂ carbons: 61.12, 39.35, 33.24 & 32.46, 23.91;CH carbons: 40.25, 32.30 ppm. HPLC: 8.974 min.

Synthesis of 4-methyl-1,4,5,6-tetrahydrocyclopentapyrazole-3-carboxylicacid (11) and 5-methyl-1,4.5,6-tetrahydrocyclopentapyrazole-3-carboxylicacid (12)

Freshly prepared aq. NaOH (10 M in H₂O, 8.07 mmol) was added to astirring, room temperature solution of 9 and 10 (0.3132 g, 1.61 mmol) inMeOH (4.0 mL, 0.4 M) under N₂. The reaction was then heated to refluxuntil the reaction was judged complete by TLC. The reaction wasconcentrated and then dissolved in 3 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 0.1781 g (66.4%) of a mixture of 11 and12. ¹H (CD₃OD, 400 MHz): δ 3.34-3.16, 3.02-2.84, 2.80-2.58, 2.40-2.26,2.10-1.98, 1.28 & 1.20 (3H, d, J=7.0 & 6.3 Hz) ppm. ¹³C (CD₃OD, 100MHz): δ 162.36 & 162.19, 158.43 & 158.43, 133.52, 128.16, 40.37 & 39.18,32.39 & 32.06, 32.03 & 22.91, 20.61 & 19.68 ppm. DEPT (CD₃OD, 100 MHz):CH₃ carbons: 20.61 & 19.68; CH₂ carbons: 39.18, 32.39 & 32.06, 22.91; CHcarbons: 40.37, 32.03 ppm. LCMS: 167.4 (M+1); 149.4 ((M+1)-18): HPLC:6.984 min.

Example 4 Synthesis of1,4,5,6,7,8-Hexahydrocycloheptapyrazole-3-carboxylic acid (15)

Synthesis oxo-(2-oxocycloheptyl)-acetic acid ethyl ester (13)

Cycloheptanone (1.9998 g, 17.8 mmol) and diethyloxalate (2.42 mL, 17.8mmol) were mixed together, and then added to a solution of NaOEt (˜3 M,5.94 mL) stirring in an ice bath under N₂. After stirring for 15minutes, the reaction was warmed to room temperature and stirredovernight. The reaction was quenched at 0° C. with 1N HCl and extracted2× with CH₂Cl₂. The combined organics were washed with H₂O, dried withNa₂SO₄, filtered, and concentrated to yield crude 13. The crude materialwas purified with 1:1 Hexanes:CH₂Cl₂ to obtain 1.9775 g (52.3%) of 13.Note: The product was still not completely pure at this point, but wascarried on to the next step. ¹H (CDCl₃, 400 MHz): δ 4.31 (2H, q, J=7.3Hz), 2.66-2.58 (2H, m), 2.48-2.43 (2H, m), 1.77-1.59 (6H, m), 1.34 (3H,t, J=7.3H) ppm.

Synthesis of 1,4,5,6,7,8-Hexahydrocycloheptapyrazole-3-carboxylic acidethyl ester (14)

Hydrazine hydrate (0.142 mL, 2.94 mmol) was added to a stirring roomtemperature solution of 13 (0.6229 g, 2.94 mmol) in EtOH (2.9 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby TLC (4.5 h): The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 70:30:2 Hexanes:CH₂Cl₂:2N NH₃ inEtOH): Only pure fractions were combined and concentrated to obtain0.4428 g (72.3%) of 14. ¹H (CDCl₃, 400 MHz): δ 8.56 (1H, broad s), 4.30(2H, q, J=7.1 Hz), 2.92-2.86 (2H, m), 2.73-2.78 (2H, m), 1.84-1.76 (2H,m), 1.65-1.57 (4H, m), 1.30 (3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz):δ 162.11, 150.70, 134.97, 124.58, 60.85, 32.33, 28.63, 28.32, 27.39,24.42, 14.47 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons: 14.47; CH₂carbons: 60.85, 32.33, 28.63, 28.32, 27.39, 24.42; ppm. HPLC: 9.19 min.

Synthesis of 1,4,5,6,7,8-Hexahydrocycloheptapyrazole-3-carboxylic acid(15)

Freshly prepared aq. NaOH (10 M in H₂O, 9.66 mmol) was added to astirring, room temperature solution of 14 (0.4029 g, 1.93 mmol) in MeOH(4.8 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by TLC (0.5 h): The reaction wasconcentrated and then dissolved in 3.8 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 15. Note: An undesired impurity thatdoes not crash out of solution upon HCl addition has a retention time of8.708 min by HPLC. ¹H (CD₃OD, 400 MHz): δ 2.98-2.90 (2H, m), 2.80-2.72(2H, m), 1.92-1.82 (2H, m), 1.70-1.58 (4H, m) ppm. ¹³C (CD₃OD, 100 MHz):δ 164.81, 151.31, 136.87, 125.13, 33.36, 29.73, 28.78, 28.49, 25.17 ppm.DEPT (CD₃OD, 100 MHz): CH₂ carbons: 33.36, 29.73, 28.78, 28.49, 25.17ppm. HPLC: 7.545 min.

Example 5 Synthesis of 5-(4-methylpentyl)-1H-pyrazole-3-carboxylic acid(18)

Synthesis of 8-methyl-2,4-dioxononanoic acid ethyl ester (16)

6-Methyl-2-heptanone (0.9981 g, 7.80 mmol) and diethyloxalate (1.06 mL,7.80 mmol) were mixed together, and then added to a solution of NaOEt(˜3 M, 2.6 mL) stirring in an ice bath under N₂. After stirring for 15minutes, the reaction was warmed to room temperature and stirredovernight. The reaction was quenched at 0° C. with 1N HCl and extracted2× with CH₂Cl₂. The combined organics were washed with H₂O, dried withNa₂SO₄, filtered, and concentrated to yield crude 16. The crude materialwas purified with 1:1 Hexanes:CH₂Cl₂ to obtain 0.8342 g (46.9%) of 16.¹H (CD₃OD, 400 MHz): δ 6.36 (1H, s), 4.30 (2H, q, J=7.1 Hz), 2.50 (2H,t, J=7.3 Hz), 1.68-1.59 (2H, m), 1.61-1.50 (1H, m), 1.33 (3H, t, J=7.1Hz), 1.25-1.17 (2H, m), 0.89 (6H, d, J=7.0 Hz) ppm. ¹³C (CD₃OD, 100MHz): δ 204.41, 166.93, 163.28, 102.66, 63.29, 41.89, 39.41, 28.92,23.65, 22.89, 14.33 ppm.

Synthesis of 5-(4-methylpentyl)-1H-pyrazole-3-carboxylic acid ethylester (17)

Hydrazine hydrate (0.943 mL, 1.91 mmol) was added to a stirring roomtemperature solution of 16 (0.4354 g, 1.91 mmol) in EtOH (1.9 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby TLC. The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 96:4 Hexanes:2N NH₃ in EtOH): Onlypure fractions were combined and concentrated to obtain 0.3132 g (63.1%)of 17. ¹H (CDCl₃, 400 MHz): δ 9.60 (1H, broad s), 6.58 (1H, s), 4.34(2H, q, J=7.2 Hz), 2.66 (2H, t, J=7.7 Hz), 1.67-1.57 (2H, m), 1.58 (1H,m), 1.36 (3H, t, J=7.2 Hz), 1.24-1.15 (2H, m), 0.85 (6H, d, J=6.5 Hz)ppm. Partial ¹³C (CDCl₃, 100 MHz): δ 162.22, 106.59, 61.17, 38.58,27.99, 27.20, 26.57, 22.72, 14.48 ppm. DEPT (CDCl₃, 100 MHz): CH₃carbons: 22.72, 14.48; CH₂ carbons: 61.17, 38.58, 27.20, 26.57; CHcarbons: 106.59, 27.99 ppm. HPLC: 10.072 min.

Synthesis of 5-(4-methylpentyl)-1H-pyrazole-3-carboxylic acid (18)

Freshly prepared aq. NaOH (10 M in H₂O, 4.97 mmol) was added to astirring, room temperature solution of 17 (0.2229 g, 0.994 mmol) in MeOH(12.4 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by HPLC (20 min): The reaction wasconcentrated and then dissolved in 2.0 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 0.1565 g (80.2%) of 18. ¹H (CD₃OD, 400MHz): δ 6.56 (1H, s), 2.68 (2H, t, J=7.6 Hz), 1.67 (2H, quint, J=7.8Hz), 1.63-1.51 (1H, m), 1.23 (2H, dt, J=8.8, 7.1 Hz), 0.89 (6H, d, J=6.4Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ 163.79, 149.69, 142.80, 107.65, 39.46,28.92, 28.11, 26.90, 22.91 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons:22.91; CH₂ carbons: 39.46, 28.11, 26.90; CH carbons: 107.65, 28.92 ppm.HPLC: 8.579 min.

Example 6 Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid (21)

Synthesis of 2,4-dioxo-6-phenylhexanoic acid ethyl ester (19)

Benzylacetone (1.0 g, 6.75 mmol) and diethyloxalate (0.92 mL, 6.75 mmol)were mixed together, and then added to a solution of NaOEt (˜3 M, 2.3mL) stirring in an ice bath under N₂. After stirring for 15 minutes, thereaction was warmed to room temperature and stirred overnight. Thereaction was quenched at 0° C. with 1N HCl and extracted 2× with CH₂Cl₂.The combined organics were washed with H₂O, dried with Na₂SO₄, filtered,and concentrated to yield crude 19. The crude material was purified with1:1 Hexanes:CH₂Cl₂ to obtain 0.7348 g (43.9%) of 19. ¹H (CD₃OD, 400MHz): δ 7.27-7.12 (5H, m), 4.26 (2H, q, J=7.2Hz), 2.89 (2H, t, J=7.3Hz), 2.81 (2H, t, J=7.3 Hz), 1.30 (3H, t, J=7.1 Hz) ppm. Partial ¹³C(CD₃OD, 100 MHz): δ 163.32, 141.74, 129.43, 129.29, 127.16, 126.95,103.06, 63.34, 43.46, 31.34, 14.24 ppm. DEPT (CD₃OD, 100 MHz): CH₃carbons: 14.24; CH₂ carbons: 63.34, 43.46, 31.34; CH carbons: 129.43,129.29, 127.16, 103.06 ppm. HPLC: 10.279 min.

Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid ethyl ester (20)

Hydrazine hydrate (0.109 mL, 2.24 mmol) was added to a stirring roomtemperature solution of 19 (0.5570 g, 2.24 mmol) in EtOH (2.2 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC. The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 70:30:2 Hexanes:CH₂Cl₂:2N NH₃ inEtOH). Only pure fractions were combined and concentrated to obtain0.2983 g (54.4%) of 20. ¹H (CDCl₃, 400 MHz): δ 11.7 (1H, broad s),7.30-7.11 (5H, m), 6.60 (1H, s), 4.32 (2H, q, J=7.1 Hz), 3.07-2.92 (4H,m), 1.31 (3H, t, J=7.1 Hz) ppm. Partial ¹³C (CDCl₃, 100 MHz): δ 162.13,147.42, 140.97, 128.72, 128.59, 126.48, 106.79, 61.16, 35.63, 28.18,14.47 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.47; CH₂ carbons:61.16, 35.63, 28.18; CH carbons: 128.72, 128.59, 126.48, 106.79 ppm.HPLC: 9.299 min.

Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid (21)

Freshly prepared aq. NaOH (10 M in H₂O, 5.06 mmol) was added to astirring, room temperature solution of 17 (0.2477 g, 1.01 mmol) in MeOH(2.5 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by HPLC (30 min). The reaction wasconcentrated and then dissolved in 2.0 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 21. Note: An undesired impurity thatdoes not crash out of solution upon HCl addition has a retention time of8.919 min by HPLC. ¹H (CD₃OD, 400 MHz): δ 7.28-7.20 (2H, m), 7.20-6.92(3H, m), 6.66 (1H, s), 3.02-2.92 (4H, m) ppm. ¹³C (CD₃OD, 100 MHz): δ164.79, 148.33, 142.96, 142.11, 129.45, 129.43, 127.21, 107.51, 36.56,28.97 ppm. DEPT (CD₃OD, 100 MHz): CH₂ carbons: 36.50, 28.91; CH carbons:129.45, 129.43, 127.24, 107.60 ppm. HPLC: 8.050 min.

Example 7 Synthesis of5-[2-(4-Methoxyphenyl)-ethyl]-1H-pyrazole-3-carboxylic acid (24)

Synthesis of 6-(4-methoxyphenyl)-2,4-dioxohexanoic acid ethyl ester (22)

4-(4-methoxyphenyl)-2-butanone (14.9908 g, 84.2 mmol) and diethyloxalate(12.3434 g, 84.2 mmol) were mixed together, and then added to a solutionof NaOEt (˜3 M, 28.1 mL) stirring in an ice bath under N₂. Afterstirring for 15 minutes, the reaction was warmed to room temperature andstirred. After 10 min, the reaction completely solidified. An additional100 mL EtOH was added, the reaction was placed on mechanical shakerovernight. The reaction was quenched at 0° C. with 1N HCl and extracted2× with CH₂Cl₂. The combined organics were washed with H₂O, dried withNa₂SO₄, filtered, and concentrated to yield crude 22. The crude materialwas purified with 1:1 Hexanes:CH₂Cl₂ to obtain 22. ¹H (CDCl₃, 400 MHz):δ 14.39 (11H, broad s), 7.10 (2H, d, J=7.1 Hz), 6.82 (2H, d, J=6.3 Hz),6.34 (1H, s), 4.33 (2H, q, J=7.1 Hz), 3.77 (3H, s), 2.91 (2H, t, J=7.3Hz), 2.78 (2H, t, J=7.3 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100MHz): δ 202.53, 166.46, 162.29, 158.36, 132.36, 129.44, 114.20, 102.11,62.75, 55.47, 43.02, 29.94, 14.27 ppm. DEPT (CDCl₃, 100 MHz): CH₃carbons: 55.47, 14.27; CH₂ carbons: 62.75, 43.02, 29.94; CH carbons:129.44, 114.20, 102.11 ppm. HPLC: 10.12 min. (Starting material: HPLC:9.10 min.)

Synthesis of 5-[2-(4-Methoxyphenyl)-ethyl]-1H-pyrazole-3-carboxylic acidethyl ester (23)

Hydrazine hydrate (0.513 mL, 10.6 mmol) was added to a stirring roomtemperature solution of 22 (2.9241 g, 10.5 mmol) in EtOH (10.6 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC (45 min): The reaction was concentrated and crystallized fromEtOH to obtain 23. ¹H (CDCl₃, 400 MHz): δ 11.67 (1H, broad s), 7.06 (2H,d, J=8.3 Hz), 6.78 (2H, d, J=8.3 Hz), 6.57 (1H, s), 4.30 (2H, q, J=7.0Hz), 3.76 (3H, s), 2.98 (2H, t, J=7.7 Hz), 2.88 (2H, t, J=7.7 Hz), 1.30(3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 162.20, 158.13, 147.05,141.79, 132.94, 129.42, 113.98, 106.61, 61.02, 55.36, 34.65, 28.23,14.37 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 55.36, 14.37; CH₂carbons: 61.02, 34.65, 28.23; CH carbons: 129.42, 113.98, 106.61 ppm.HPLC: 9.200 min.

Synthesis of 5-[2-(4-Methoxyphenyl)-ethyl]-1H-pyrazole-3-carboxylic acid(24)

Freshly prepared aq. NaOH (10 M in H₂O, 25.4 mmol) was added to astirring, room temperature solution of 23 (1.391 g, 5.07 mmol) in MeOH(12.7 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by HPLC (30 min): The reaction wasconcentrated and then dissolved in 10 mL H₂O. The reaction was extractedwith a small amount of EtOAc, then the aqueous layer was made acidic(pH=2) with the dropwise addition of 10% aq. HCl. The white solid thatprecipitated from the reaction was filtered off and washed with coldH₂O. The solid was dried under vacuum overnight to obtain 0.3771 g ofrelatively pure 24. 24 was further purified by recrystallization fromwarm MeOH to obtain 0.1317 g of pure 24. No attempts were made torecover remaining 24 from the mother liquor. ¹H (CD₃OD, 400 MHz): 7.07(2H, d, J=8.2 Hz), 6.84 (2H, d, J=8.6 Hz), 6.53 (1H, s), 3.73 (3H, s),2.97-2.84 (4H, m) ppm. ¹³C (CD₃OD, 100 MHz): δ 164.86, 159.60, 148.26,143.15, 134.01, 130.36, 114.81, 107.50, 55.60, 35.67, 29.10 ppm.

Example 8 Synthesis of 4-Benzyl-1H-pyrrole-2-carboxylic acid methylester (26)

Synthesis of 4-Benzyl-1H-pyrrole-2-carboxylic acid methyl ester (25)

Triethylsilane (0.215 mL, 1.35 mmol) was added to a stirring, roomtemperature solution of methyl-4-benzoyl-1H-pyrrole-2-carboxylate(0.1118 g, 0.488 mmol) in trifluoroacetic acid (TFA) (1.04 mL, 0.47 M)under N₂. After stirring overnight, the reaction was complete by HPLC.The TFA was removed under vacuum, and the crude product was taken up inEtOAc, washed with brine, dried with Na₂SO₄, filtered, concentrated, andpurified by silica gel chromatography (Combiflash column, 95:5Hexanes:EtOAc) to obtain pure 25 (0.0604 g, 57.5%): ¹H (CDCl₃, 400 MHz):δ 9.44 (11H, broad s), 7.34-7.21 (5H, m), 6.78 (1H, s), 6.75 (1H, s),3.853 (2H, s), 3.846 (3H, s) ppm. ¹³C (CDCl₃, 100 MHz): δ 162.09,141.68, 128.85, 128.70, 126.25, 125.55, 122.67, 121.86, 115.74, 51.70,33.41 ppm. HPLC: 9.693 min. (Starting material: 8.611 min.)

Synthesis of 4-Benzyl-1H-pyrrole-2-carboxylic acid methyl ester (26)

Freshly prepared aq. NaOH (10 M in H₂O, 1.40 mmol) was added to astirring, room temperature solution of 25 (0.0602 g, 0.280 mmol) in MeOH(0.70 mL, 0.4 M) under N₂. Another 0.7 mL of MeOH was added due toprecipitation of the starting material, and the reaction was heated toreflux until the reaction was judged complete by HPLC. The reaction wasconcentrated and then dissolved in 0.55 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 0.0495 g (94.5%) of 26. ¹H (CD₃OD, 400MHz): δ 10.83 (1H, broad s), 7.27-7.11 (5H, m), 6.71 (1H, s), 6.66 (1H,s), 3.78 (2H, s) ppm. ¹³C (CD₃OD, 100 MHz): δ 164.45, 143.25, 129.58,129.31, 126.81, 126.18, 123.70, 122.96, 116.68, 34.03 ppm. DEPT (CD₃OD,100 MHz): CH₂ carbons: 34.03; CH carbons: 129.58, 129.31, 126.81,122.96, 116.68 ppm. HPLC: 8.647 min.

Example 9 Synthesis of 4-Phenethyl-1H-pyrrole-2-carboxylic acid (28)

Synthesis of 4-Phenethyl-1H-pyrrole-2-carboxylic acid methyl ester (27)

Triethylsilane (0.323 mL, 2.03 mmol) was added to a stirring, roomtemperature solution of methyl-4-phenylacetyl-1H-pyrrole-2-carboxylate(0.1593 g, 0.655 mmol) in trifluoroacetic acid (TFA) (1.47 mL, 0.45 M)under N₂. After stirring overnight, the reaction was complete by HPLC.The TFA was removed under vacuum, and the crude product was taken up inEtOAc, washed with brine, dried with Na₂SO₄, filtered, concentrated, andpurified by silica gel chromatography (Combiflash column, 95:5Hexanes:EtOAc) to obtain pure 27 (0.0755 g, 50.3%): ¹H (CDCl₃, 400 MHz):δ 9.17 (1H, broad s), 7.32-7.25 (2H, m), 7.23-7.17 (3H, m), 6.80 (1H,s), 6.69 (1H, s), 3.85 (3H, s), 2.93-2.85 (2H, m), 2.84-2.75 (2H, m)ppm. ¹³C (CDCl₃, 100 MHz): δ 161.97, 142.15, 128.70, 128.55, 126.13,125.96, 122.40, 121.26, 115.28, 51.67, 37.57, 28.92 ppm. DEPT (CDCl₃,100 MHz): CH₃ carbons: 51.67; CH₂ carbons: 37.57, 28.92; CH carbons:128.70, 128.55, 126.13, 121.26, 115.28 ppm. HPLC: 10.033 min. (Startingmaterial: 8.751 min.)

Synthesis of 4-Phenethyl-1H-pyrrole-2-carboxylic acid (28)

Freshly prepared aq. NaOH (10 M in H₂O, 1.65 mmol) was added to astirring, room temperature solution of 27 (0.0755 g, 0.329 mmol) in MeOH(0.82 mL, 0.4 M) under N₂. Another 0.7 mL of MeOH was added due toprecipitation of the starting material, and the reaction was heated toreflux until the reaction was judged complete by HPLC (2 h): Thereaction was concentrated and then dissolved in 0.55 mL H₂O. 10% aq. HClwas added dropwise until the pH=2. The white solid that precipitatedfrom the reaction was filtered off and washed with cold H₂O. The solidwas dried under vacuum overnight to obtain pure 28. ¹H (CDCl₃, 400 MHz):δ 10.87 (1H, broad s), 7.25-7.18 (2H, m), 7.17-7.69 (3H, m), 6.70 (1H,s), 6.67 (1H, s), 2.83 (2H, t, J=7.6 Hz), 2.74 (2H, t, J=7.6 Hz) ppm.¹³C (CDCl₃, 100 MHz): δ 164.53, 143.39, 129.50, 129.21, 126.76, 126.38,123.49, 122.85, 116.48, 38.68, 29.94 ppm. DEPT (CDCl₃, 100 MHz): CH₂carbons: 38.68, 29.94; CH carbons: 129.50, 129.21, 126.76, 122.85,116.48 ppm. HPLC: 8.579 min.

Example 10 Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid (32)

Synthesis of 5-benzoyl-1H-pyrrole-2-carboxylic acid ethyl ester (29) and4-benzoyl-1H-pyrrole-2-carboxylic acid ethyl ester (30)

Ethylpyrrole-2-carboxylate (1.0013 g, 7.20 mmol) in a minimal amount(2.5 mL) of dichloroethane was added to an ice cooled stirring mixtureof zinc chloride (1.96 g, 14.4 mmol) and benzoyl chloride (1.67 mL, 14.4mmol) in dichloroethane (10.9 mL, 0.66 M) under N₂. After stirring 10min, the ice bath was removed, and the reaction was heated to 50° C.until it was judged complete by TLC (35 min, 9:1 Hexanes:EtOAc): Thereaction was the cooled, and carefully poured onto ice water. Thereaction was extracted into CH₂Cl₂ with 3 portions of solvent. Thecombined organics were washed with H₂O, dilute HCl, and brine, thendried with Na₂SO₄, filtered, concentrated, and purified by silica gelchromatography (Combiflash column, 95:5 to 50:50 Hexanes:EtOAc) toobtain 29 (higher Rf) and pure 30 (lower Rf, 0.5646 g, 32.3%): 29 wasfurther purified by silica gel chromatography (Combiflash column, 100%CH₂Cl₂) to achieve 0.6168 g (35.2%) of 29.

Spectral data for 29: ¹H (CDCl₃, 400 MHz): δ 10.19 (1H, broad s), 7.90(2H, d, J=7.6 Hz), 7.59 (1H, t, J=7.3 Hz), 7.49 (2H, t, J=7.3 Hz), 6.94(1H, dd, J=3.9, 2.4 Hz), 6.83 (1H, dd, J=3.9, 2.4 Hz), 4.38 (2H, q,J=7.0 Hz), 1.38 (3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 185.37,160.56, 137.69, 133.30, 132.72, 129.27, 128.69, 127.97, 118.75, 115.72,61.39, 14.55 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.55; CH₂carbons: 61.39; CH carbons: 132.72, 129.27, 128.69, 118.75, 115.72 ppm.HPLC: 9.792 min. (Starting material: 8.36 min.)

Spectral data for 30: ¹H (CDCl₃, 400 MHz): δ 10.29 (1H, broad s), 7.84(2H, dd, J=8.0, 1.2 Hz), 7.59-7.53 (2H, m), 7.48 (2H, t, J=7.6 Hz), 7.36(1H, dd, J=2.4, 1.5 Hz), 4.38 (2H, t, J=7.3 Hz), 1.35 (3H, t, J=7.3 Hz)ppm. ¹³C (CDCl₃, 100 MHz): δ 190.93, 161.47, 139.21, 132.23, 129.22,128.77, 128.61, 124.35, 116.91, 112.82, 61.30, 14.55 ppm. DEPT (CDCl₃,100 MHz): CH₃ carbons: 14.55; CH₂ carbons: 61.30; CH carbons: 132.23,129.22, 128.77, 128.61, 116.91 ppm. HPLC: 9.048 min.

Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid ethyl ester (31)

Triethylsilane (0.323 mL, 2.03 mmol) was added to a stirring, roomtemperature solution of 5-benzoyl-1H-pyrrole-2-carboxylic acid ethylester (29) (0.4180 g, 1.72 mmol) in trifluoroacetic acid (TFA) (4.1 mL,0.42 M) under N₂. After stirring overnight, the reaction did not appearto be complete by HPLC. Addition of addition quantities oftriethylsilane did not result in any further changes by HPLC, so thereaction was worked up. The TFA was removed under vacuum, and the crudeproduct was taken up in EtOAc, washed with brine, dried with Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography(Combiflash column, 98:2 to 95:5 Hexanes:EtOAc) to obtain pure 31(0.2190 g, 55.6%). ¹H (CDCl₃, 400 MHz): δ 9.05 (1H, broad s), 7.35-7.28(2H, m), 7.28-7.23 (1H, m), 7.23-7.18 (2H, m), 6.85 (1H, t, J=3.2Hz),6.0 (1H, t, J=3.2 Hz), 4.27 (2H, q, J=7.1 Hz), 4.00 (2H, s), 1.32 (3H,t, J=7.3 Hz) ppm. Partial ¹³C (CDCl₃, 100 MHz): δ 138.51, 136.86,128.99, 128.88, 126.98, 122.26, 116.08, 109.41, 60.39, 34.37, 14.70 ppm.DEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.70; CH₂ carbons: 60.39, 34.37; CHcarbons: 128.99, 128.88, 126.98, 116.08, 109.41 ppm. HPLC: 10.014 min.

Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid (32)

Freshly prepared aq. NaOH (10 M in H₂O, 4.78 mmol) was added to astirring, room temperature solution of 31 (0.2190 g, 0.955 mmol) in MeOH(2.4 mL, 0.4 M) under N₂. The reaction was heated to reflux until thereaction was judged complete by HPLC (40 min). The product wasconcentrated and then dissolved in 1.9 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 32 as a pale pink, impure solid (0.0845g). 32 was further purified by adding CHCl₃, stirring, and filtering offpure white 32 (0.0445 g). Note. The undesired impurity has a retentiontime of 9.643 min by HPLC. Also, the ¹³C NMR of 32 at room temperatureshowed doublets for the peaks corresponding to the pyrrole carbons,benzyl carbon, and acid carbon. When the NMR probe was heated to 28° C.,all doubled peaks collapsed into single peaks as reported below. ¹H(CD₃OD, 400 MHz): δ 11.04 (1H, broad s), 7.27-7.13 (5H, m), 6.80 (1H, d,J=3.4 Hz), 5.87 (1H, d, J=3.4 Hz) 3.93 (2H, s) ppm. ¹³C (CD₃OD, 100MHz): δ 164.52, 140.71, 139.04, 129.56, 129.42, 127.27, 122.77, 117.59,109.66, 34.65 ppm. DEPT (CD₃OD, 100 MHz): CH₂ carbons: 34.65; CHcarbons: 129.56, 129.42, 127.27, 117.59, 109.66 ppm. HPLC: 8.698 min.

Example 11 Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid (36)

Synthesis of 5-phenylacetyl-1H-pyrrole-2-carboxylic acid ethyl ester(33) and 4-phenylacetyl-1H-pyrrole-2-carboxylic acid ethyl ester (34)

Ethylpyrrole-2-carboxylate (2.5182 g, 18.1 mmol) in a minimal amount ofdichloroethane was added to an ice cooled stirring mixture of zincchloride (4.9891 g, 36.6 mmol) and phenylacetyl chloride (4.76 mL, 35.9mmol) in dichloroethane (25 mL, 0.72 M) under N₂. After stirring 10 min,the ice bath was removed, and the reaction was heated to 50° C. until itwas judged complete by TLC (30 min., 9:1 Hexanes:EtOAc): The reactionwas the cooled, and carefully poured onto ice water. The reaction wasextracted into CH₂Cl₂ with 3 portions of solvent. The combined organicswere washed with H₂O, dilute HCl, and brine, then dried with Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography(Combiflash column, 90:10 to 60:40 Hexanes:EtOAc) to obtain 33 (lowerRf) and 34 (higher Rf): 33 was found to contain a colored impurity thatwas easily removed by adding hexanes and removing the colored solution.Following treatment with hexanes, 33 (0.7239g, 15.5%) was sufficientlypure to continue to the next step.

Spectral data for 33: ¹H (CDCl₃, 400 MHz): δ 9.87 (1H, broad s),7.35-7.23 (5H, m), 6.92-6.87 (2H, m), 4.34 (2H, q, J=7.1 Hz), 4.09 (2H,s), 1.36 (3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 188.72, 160.49,134.40, 133.63, 129.57, 128.96, 127.82, 127.32, 116.60, 115.73, 61.39,45.59, 14.54 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.54; CH₂carbons: 61.39, 45.59; CH carbons: 129.57, 128.96, 127.32, 116.60,115.73 ppm. HPLC: 9.714 min. (Starting material: 8.36 min.)

Spectral data for 34: ¹H (CDCl₃, 400 MHz): δ 10.16 (1H, broad s), 7.74(1H, s), 7.72 (1H, s), 7.44-7.23 (5H, m), 4.33 (2H, q, J=7.1 Hz), 4.18(2H, s), 1.34 (3H, t, J=7.1 Hz) ppm. Partial ¹³C (CDCl₃, 100 MHz): δ193.45, 160.64, 61.43, 47.97, 14.49 ppm. HPLC: 10.7 min.

Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (35)

Triethylsilane (0.46 mL, 2.88 mmol) was added to a stirring, roomtemperature solution of 5-phenylacetyl-1H-pyrrole-2-carboxylic acidethyl ester (33) (0.240 g, 0.929 mmol) in trifluoroacetic acid (TFA)(2.2 mL, 0.42 M) under N₂. The reaction was judged complete by HPLCafter 3.5 h. The TFA was removed under vacuum, and the crude product wastaken up in EtOAc, washed with brine, dried with Na₂SO₄, filtered,concentrated, and purified by silica gel chromatography (Combiflashcolumn, 60:40 Hexanes:CH₂Cl₂ to obtain 35, which appeared pure by TLC,but impure by HPLC. Pure 35 was obtained by preparative reverse phaseHPLC with the following conditions: 0 to 10 min, 35:65 H₂O: CH₃CN. 10-11min, 35:65 to 0:100 H₂O: CH₃CN; 20 mL/min.; λ=254 nM; 50.8 mg/mL, 0.8mL/injection. ¹H (CDCl₃, 400 MHz): 9.46 (1H, broad s), 7.33-7.16 (5H,m), 6.85 (1H, t, J=2.9 Hz), 5.99 (1H, t, J=2.9 Hz), 4.29 (2H, q, J=7.1Hz), 2.97 (4H, s), 1.33 (3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ161.76, 141.16, 138.18, 128.69, 128.52, 126.46, 121.52, 116.06, 108.46,60.36, 35.89, 29.83, 14.67 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons:14.67; CH₂ carbons: 60.36, 35.89, 29.83; CH carbons: 128.69, 128.52,126.46, 116.06, 108.46 ppm. HPLC: 10.392 min.

Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid (36)

Freshly prepared aq. NaOH (10 M in H₂O, 1.67 mmol) was added to astirring, room temperature solution of 35 (0.0814 g, 0.333 mmol) in MeOH(0.83 mL, 0.4 M) under N₂. 0.4 mL of iPrOH was added to solubilize 35.The reaction was heated to reflux until the reaction was judged completeby HPLC. The product was concentrated and then dissolved in 1.9 mL H₂O.10% aq. HCl was added dropwise until the pH=2. The white solid thatprecipitated from the reaction was filtered off and washed with coldH₂O. The solid was dried under vacuum overnight to obtain 36 as a palepink solid (Note: An undesired impurity has a retention time of 12.055min by HPLC. Also, the ¹³C NMR of 36 at room temperature showed doubletsfor the peaks corresponding to the pyrrole carbons, benzyl carbon, andacid carbon. When the NMR probe was heated to 28° C., all doubled peakscollapsed into single peaks as reported below. ¹H (CD₃OD, 400 MHz): δ10.97 (1H, broad s), 7.25-7.20 (2H, m), 7.18-7.11 (3H, m), 6.76 (1H, d,J=3.4 Hz), 5.90 (1H, d, J=3.4Hz), 2.94-2.84 (4H, m) ppm. ¹³C (CD₃OD, 100MHz): δ 164.51, 142.68, 139.79, 129.40, 129.30, 126.98, 122.36, 117.47,108.90, 37.00, 30.67 ppm. DEPT (CDCl₃, 100 MHz): CH₂ carbons: 37.00,30.67; CH carbons: 129.40, 129.30, 126.98, 117.47, 108.90 ppm. HPLC:11.239 min.

Example 12 Synthesis of4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (39)

Synthesis of 4-[2-(4-chlorophenyl)-acetyl-1H-pyrrole-2-carboxylic acidethyl ester (3 7)

Ethylpyrrole-2-carboxylate (1.0195 g, 7.33 mmol) in a minimal amount ofdichloroethane was added to an ice cooled stirring mixture of aluminumchloride (1.934 g, 14.5 mmol) and 4-chlorobenzeneacetyl chloride (2.7841g, 14.73 mmol) in dichloroethane (10.9 mL, 0.67 M) under N₂. Afterstirring 10 min, the ice bath was removed, and the reaction was stirredat room temperature for 60 minutes, with little change by TLC (9:1Hexanes:EtOAc): After heating to 60° C. for an additional hour, only asmall quantity of starting material was left by TLC. The reaction wascooled to room temperature, PS-Trisamine™ resin (6.3954 g, 24.30 mmol)and dichloroethane (10 mL) were added, and the reaction was stirred for3 hours. The reaction was then filtered through a glass-fritted funneldirectly into ice water. The resin was rinsed with CH₂Cl₂, then theorganic layers were removed, dried with Na₂SO₄, filtered, concentrated,and purified by silica gel chromatography (Combiflash column, 95:5 to50:50 Hexanes:EtOAc) to obtain 1.0345 g (48.4%) 37 as a pale orangesolid. Note: A small amount of CH₂Cl₂ was required to solubilize thecrude product before placement on the silica column. ¹H (CDCl₃, 400MHz): δ 10.07 (1H, broad s), 7.55-7.52 (1H, m), 7.33-7.30 (1H, m), 7.27(2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz), 4.35 (2H, q, J=7.0 Hz), 4.04(2H, s), 1.37 (3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ]192.55,160.97, 133.10, 132.75, 130.76, 128.69, 126.80, 126.25, 124.30, 114.95,61.06, 45.79, 14.31 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.31; CH₂carbons: 61.06, 45.79; CH carbons: 130.76, 128.69, 126.80, 114.96 ppm.HPLC: 10.049 min.

Synthesis of 4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acidethyl ester (38)

Triethylsilane (1.13 mL, 7.08 mmol) was added to a stirring, roomtemperature solution of4-[2-(4-chlorophenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester(37) (0.6662 g, 2.28 mmol) in trifluoroacetic acid (TFA) (5.54 mL, 0.42M) under N₂. After stirring at room temperature for 4 hours, the TFA wasremoved under vacuum, and the crude product was taken up in EtOAc,washed with brine, dried with Na₂SO₄, filtered, concentrated, andpurified by preparative reverse phase HPLC with the followingconditions: 0 to 12 min, 35:65 H₂O: CH₃CN. 12-13 min, 35:65 to 0:100H₂O: CH₃CN; 20 mL/min.; λ=254 nM; 137 mg/mL, 1.0 mL/injection. 0.2704 g(42.6%) of 38 was obtained as a fluffy white solid. (Note: An undesiredimpurity has a retention time of 12.055 min by HPLC.) ¹H (CDCl₃, 400MHz): δ 8.99 (1H, broad s), 7.23 (2H, d, J=8.3 Hz), 7.09 (2H, d, J=8.3Hz), 6.76 (1H, s), 6.64 (1H, s), 4.30 (2H, q, J=7.0 Hz), 2.84 (2H, t,J=7.6 Hz), 2.75 (2H, t, J=7.6 Hz), 1.35 (3H, t, J=7.1 Hz) ppm. ¹³C(CDCl₃, 100 MHz): δ 161.14, 140.25, 131.52, 129.80, 128.32, 125.17,122.62, 120.66, 114.73, 60.25, 36.62, 28.53, 14.43 ppm. DEPT (CDCl₃, 100MHz): CH₃ carbons: 14.43; CH₂ carbons: 60.25, 36.62, 28.53; CH carbons:129.80, 128.32, 120.66, 114.73 ppm. HPLC: 11.049 min.

Synthesis of 4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid(39)

Freshly prepared aq. NaOH (10 M in H₂O, 4.84 mmol) was added to astirring, room temperature solution of 38 (0.2689 g, 0.968 mmol) in MeOH(2.42 mL, 0.4 M) under N₂. The reaction was heated to reflux until thereaction was judged complete by HPLC (30 min): The product wasconcentrated and then dissolved in 5 mL H₂O. The product was extractedwith EtOAc, then the aqueous layer was made acidic (pH=2) with thedropwise addition of 10% aq. HCl. The white solid that precipitated fromthe reaction was filtered off and washed with cold H₂O. The solid wasdried under vacuum overnight to obtain 39 as a pale pink solid (Note: Anundesired impurity has a retention time of 10.956 min by HPLC. ¹H(CD₃OD, 400 MHz): δ 10.89 (1H, broad s), 7.22 (2H, d, J=8.3 Hz), 7.13(2H, d, J=8.3 Hz), 6.69 (1H, s), 6.66 (1H, s), 2.82 (2H, t, J=7.1 Hz),2.73 (2H, t, J=7.1 Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ 164.48, 142.15,132.49, 131.15, 129.21, 125.97, 123.60, 122.88, 116.44, 37.92, 29.70ppm. DEPT (CDCl₃, 100 MHz): CH₂ carbons: 37.92, 29.70; CH carbons:131.15, 129.21, 122.88, 116.44 ppm. HPLC: 9.996 min.

Example 13 Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid(42)

Synthesis of 2,4-dioxo-5-phenoxypentanoic acid ethyl ester (40)

Phenoxyacetone (5.0240 g, 33.46 mmol) and diethyloxalate (4.52 mL, 33.29mmol) were mixed together, and then added to a solution of NaOEt (˜3 M,11.1 mL) stirring in an ice bath under N₂. After stirring for 15minutes, the reaction was warmed to room temperature and stirredovernight. The reaction was quenched at 0° C, with 1N HCl and extracted2× with CH₂Cl₂. The combined organics were washed with H₂O, dried withNa₂SO₄, filtered, and concentrated to yield crude 40. The crude materialwas purified with 1:1 Hexanes:CH₂Cl₂ to obtain 1.3490 g (15.4%) of 40.¹H (CDCl₃, 400 MHz): δ 7.31 (2H, t, J=7.5 Hz), 7.01 (1H, t, J=7.3 Hz),6.91 (2H, d, J=8.8 Hz), 6.76 (1H, s), 4.67 (2H, s), 4.35 (2H, q, J=7.1Hz), 1.38 (3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 199.61, 166.38,161.55, 157.37, 129.63, 121.89, 114.48, 98.97, 70.13, 62.60, 13.90 ppm.DEPT (CDCl₃, 100 MHz): CH₃ carbons: 13.90; CH₂ carbons: 70.13, 62.60; CHcarbons: 129.63, 121.89, 114.48, 98.97 ppm. HPLC: 10.180 min. (Startingmaterial: 9.053 min)

Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester(41)

Hydrazine hydrate (0.197 mL, 4.06 mmol) was added to a stirring roomtemperature solution of 40 (1.0163 g, 4.06 mmol) in EtOH (4.1 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC. The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 92:4:4 Hexanes:CH₂Cl₂:2N NH³ inEtOH): Only pure fractions were combined and concentrated to obtain0.5474 g (54.7%) of 41. ¹H (CDCl₃, 400 MHz): δ 12.12 (1H, broad s), 7.28(2H, t, J=7.8 Hz), 7.01-6.94 (3H, m), 6.91 (1H, s), 5.17 (2H, s), 4.36(2H, q, J=7.0 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. Partial ¹³C (CDCl₃, 100MHz): δ 158.11, 129.48, 121.26, 114.71, 107.83, 62.61, 61.31, 14.17 ppm.HPLC: 9.505 min.

Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid (42)

Freshly prepared aq. NaOH (10 M in H₂O, 10.49 mmol) was added to astirring, room temperature solution of 41 (0.5164 g, 2.10 mmol) in MeOH(5.2 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by HPLC (20 min): The reaction wasconcentrated and then dissolved in 4.2 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 0.4044 g (88.4%) of 42 as a whitesolid. Note: An undesired impurity that does not crash out of solutionupon HCl addition has a retention time of 9.127 min by ¹H (CDCl₃, 400MHz): δ 7.26 (2H, t, J=8.0 Hz), 6.99 (2H, d, J=8.3 Hz), 6.94 (1H, t,J=7.3 Hz), 6.85 (1H, s), 5.10 (2H, s) ppm. 13C (CDCl₃, 100 MHz): δ163.68, 159.73, 146.60, 141.13, 130.51, 122.27, 115.83, 108.88, 63.06ppm. DEPT (CDCl₃, 100MHz): CH₂ carbons: 63.06; CH carbons: 130.51,122.27, 115.83, 108.88 ppm. HPLC: 8.272 min.

Example 14 Synthesis of 4-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid(45)

Synthesis of 4-(3-phenylpropionyl)-1H-pyrrole-2-carboxylic acid ethylester (43)

Ethylpyrrole-2-carboxylate (1.6236 g, 11.67 mmol) in a minimal amount ofdichloroethane was added to an ice cooled stirring mixture of aluminumchloride (3.1085 g, 23.30 mmol) and hydrocinnanomyl chloride (3.9058 g,23.16 mmol) in dichloroethane (17.7 mL, 0.67 M) under N₂. After stirring10 min, the ice bath was removed, and the reaction was stirred at roomtemperature for 60 minutes, with little change by TLC (9:1Hexanes:EtOAc): After heating to 60° C. for an additional hour, only asmall quantity of starting material was left by TLC. The reaction wascooled to room temperature, Polyamine resin HL (2.60 mmol/g, 16.41 g,42.67 mmol) and dichloroethane (10 mL) were added, and the reaction wasstirred for 3 hours. The reaction was then filtered through aglass-fritted funnel directly into ice water. The resin was rinsed withCH₂Cl₂, then the organic layers were removed, dried with Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography(Combiflash column, 92:8:4 Hexanes:CH₂Cl₂:2N NH₃ in EtOH) to obtain0.5501 g (14.1%) of 43 as a pale orange solid. ¹H (CDCl₃, 400 MHz): δ10.70 (1H, broad s), 7.56 (1H, s), 7.36-7.17 (6H, m), 4.35 (2H, q, J=7.0Hz), 3.18-3.10 (2H, m), 3.10-3.01 (2H, m), 1.37 (3H, t, J=7.1 Hz) ppm.¹³C (CDCl₃, 100 MHz): δ 194.98, 161.18, 141.13, 128.31, 128.20, 126.64,126.42, 125.92, 123.96, 114.72, 60.84, 41.19, 30.04, 14.16 ppm. DEPT(CDCl₃, 100 MHz): CH₃ carbons: 14.16; CH₂ carbons: 60.84, 41.19, 30.04;CH carbons: 128.31, 128.20, 126.64, 125.92, 114.72 ppm. HPLC: 9.975 min.

Synthesis of 4-(3-phenylpropyl)1H-pyrrole-2-carboxylic acid ethyl ester(44)

Triethylsilane (0.776 mL, 4.87 mmol) was added to a stirring, roomtemperature solution of 43 (0.5266 g, 1.57 mmol) in trifluoroacetic acid(TFA) (3.74 mL, 0.42 M) under N₂. After stirring at room temperature for4 hours, the TFA was removed under vacuum, and the crude product wastaken up in EtOAc, washed with brine, dried with Na₂SO₄, filtered,concentrated, and purified by preparative reverse phase HPLC with thefollowing conditions: 0 to 11 min, 35:65 H₂O:CH₃CN. 11.5-20 min, 35:65to 0:100 H₂O:CH₃CN; 20 mL/min.; λ=254 nM; 200 mg/mL, 0.7 mL/injection.0.2455 g (48.7%) of 44 was obtained as a fluffy white solid. (Note: Anundesired impurity has a retention time of 12.062 min by HPLC.) ¹H(CDCl₃, 400 MHz): δ 9.27 (1H, broad s), 7.34-7.26 (2H, m), 7.24-7.17(3H, m), 6.81 (1H, s), 6.75 (1H, s), 4.33 (2H, q, J=7.1 Hz), 2.67 (2H,t, J=7.8 Hz), 2.53 (2H, t, J=7.8 Hz), 1.93 (2H, quint, J=7.8 Hz), 1.37(3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 161.34, 142.31, 128.40,128.22, 125.99, 125.64, 122.47, 120.73, 114.82, 60.17, 35.33, 32.47,26.17, 14.41 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.41; CH₂carbons: 60.17, 35.33, 32.47, 26.17; CH carbons: 128.40, 128.22, 125.64,120.73, 114.82 ppm. HPLC: 11.140 min.

Synthesis of 4-(3-phenylpropyl)1H-pyrrole-2-carboxylic acid (45)

Freshly prepared aq. NaOH (10 M in H₂O, 3.82 mmol) was added to astirring, room temperature solution of 44 (0.2455 g, 0.7644 mmol) inMeOH (1.9 mL, 0.4 M) under N₂. The reaction was heated to reflux untilthe reaction was judged complete by HPLC (25 min): The product wasconcentrated and then dissolved in 1.5 mL H₂O. The product was extractedwith EtOAc, then the aqueous layer was made acidic (pH=2) with thedropwise addition of 10% aq. HCl. EtOAc was added, and the product wasextracted into the organic layer. The organic layer was dried withNa₂SO₄, filtered, and concentrated to obtain 56.1 mg of product thatcontained a few minor impurities by HPLC. The product was taken up intoa minimal amount of CHCl₃ with heating, and then a small amount ofhexanes was added to precipitate the product. The product was filtered,and dried to obtain 16.0 mg of 45. (Note: An undesired impurity has aretention time of 10.843 min by HPLC. ¹H (CD₃OD, 400 MHz): δ 7.24 (2H,t, J=7.3 Hz), 7.16 (2H, d, J=7.3 Hz), 7.13 (1H, t, J=7.3 Hz), 6.75 (1H,s), 6.71 (1H, s) 2.61 (2H, t, J=7.8 Hz), 2.46 (2H, t, J=7.8 Hz), 1.86(2H, quint, J=7.8 Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ 164.54, 143.73,129.47, 129.27, 126.73, 126.66, 123.49, 122.56, 116.34, 36.41, 34.23,27.21 ppm. DEPT (CDCl₃, 100 MHz): CH₂ carbons: 36.41, 34.23, 27.21; CHcarbons: 129.47, 129.27, 126.66, 122.56, 116.34 ppm. HPLC: 9.845 min.

Example 15 Synthesis of 5-(3-methylbutyl)-1H-pyrazole-3-carboxylic acid(48)

Synthesis of 7-methyl-2,4-dioxooctanoic acid ethyl ester (46)

5-methyl-2-hexanone (5.0084 g, 43.9 mmol) and diethyloxalate (5.95 mL,43.8 mmol) were mixed together, and then added to a solution of NaOEt(˜3 M, 14.6 mL) stirring in an ice bath under N₂. After stirring for 15minutes, the reaction was warmed to room temperature and stirredovernight. The reaction was quenched at 0° C. with 1N HCl and extracted2× with CH₂Cl₂. The combined organics were washed with H₂O, dried withNa₂SO₄, filtered, and concentrated to yield crude 46. The crude materialwas purified with 1:1 Hexanes:CH₂Cl₂ to obtain 6.6035 g (70.3%) of 46.¹H (CDCl₃, 400 MHz): δ 6.28 (1H, s), 4.25 (2H, q, J=7.0 Hz), 2.40 (2H,t, 7.6 Hz), 1.54-1.41 (3H, m), 1.27 (3H, t, J=7.3 Hz), 0.82 (6H, d,J=6.3 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 203.40, 166.27, 161.85, 101.37,62.15, 38.74, 33.39, 27.46, 21.99, 13.77 ppm. DEPT (CDCl₃, 100 MHz): CH₃carbons: 21.99, 13.77; CH₂ carbons: 62.15, 38.74, 33.39; CH carbons:101.37, 27.46 ppm. HPLC: 11.038min.

Synthesis of5-(3-methylbutyl)-1H-pyrazole-3-carboxylic acid ethyl ester(47)

Hydrazine hydrate (1.43 mL, 2.95 mmol) was added to a stirring roomtemperature solution of 46 (6.3112 g, 2.95 mmol) in EtOH (29.5 mL, 1 M)under N₂. The reaction was then stirred at room temperature until judgedcomplete by HPLC (35 min): The reaction was concentrated and purified bysilica gel chromatography (Combiflash column, 96:4 Hexanes:2N NH₃ inEtOH): Only pure fractions were combined and concentrated to obtain4.3911 g (70.9%) of 47. ¹H (CDCl₃, 400 MHz): δ 13.01 (1H, broad s), 6.52(1H, s), 4.29 (2H, q, J=7.1 Hz), 2.64 (2H, t, J=7.8 Hz), 1.57-1.41 (3H,m), 1.26 (3H, t, J=7.1 Hz), 5.85 (6H, d, J=5.9 Hz) ppm. ¹³C (CDCl₃, 100MHz): δ 162.37, 146.26, 143.1, 105.73, 60.53, 37.88, 27.35, 23.42,22.11, 14.06 ppm. HPLC: 10.006 min.

Synthesis of 5-(3-methylbutyl)-1H-pyrazole-3-carboxylic acid (48)

Freshly prepared aq. NaOH (10 M in H₂O, 80.85 mmol) was added to astirring, room temperature solution of 47 (3.40 g, 16.17 mmol) in MeOH(40.4 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by HPLC (6 min): The reaction wasconcentrated and then dissolved in 14 mL H₂O. 10% aq. HCl was addeddropwise until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 2.8753 g (97.6%) of 48. (Note: Anundesired impurity has a retention time of 9.522 min by HPLC.) ¹H(CDCl₃, 400 MHz): δ 6.61(1H, s), 2.70 (2H, t, J=7.8Hz), 1.63-1.51 (3H,m), 0.94 (6H, d, J=6.3 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 164.35, 149.48,143.00, 107.34 28.71, 24.69, 22.65 ppm. DEPT (CDCl₃, 100 MHz): CH₃carbons: 22.65; CH₂ carbons: 39.35, 24.69; CH carbons: 107.34, 28.71ppm. HPLC: 9.522 min.

Example 16 Synthesis of 5-(4-Methylpent-3-enyl)-1H-pyrazole-3-carboxylicacid (51)

Synthesis of 8-Methyl-2,4-dioxonon-7-enoic acid ethyl ester (49)

Sodium hydride (0.465 g, 19.4 mmol) was added slowly to a NaCl ice bathcontaining EtOH (5.88 mL, 3.3 M) stirring under N₂.6-Methylhept-5-en-2-one (2.4412 g, 19.3 mmol) and diethyloxalate (2.63mL, 19.4 mmol) were mixed together, and then added to the chilled NaOEtsolution. After stirring for 15 minutes, the reaction was warmed to roomtemperature and stirred for 6 hours, at which point the reaction wasjudged complete by TLC. The reaction was quenched at 0° C. with 1N HCland extracted 2× with CH₂Cl₂. The combined organics were washed withH₂O, dried with Na₂SO₄, filtered, and concentrated, and purified bysilica gel chromatography (Combiflash column, 70:30:3 Hexanes:CH₂Cl₂:2NNH₃ in EtOH): Only pure fractions were combined and concentrated toobtain 1.9190 g (43.8%) of 49. ¹H (CDCl₃, 400 MHz): δ 14.44 (1H, broads), 6.34 (1H, s), 5.06 (1H, t, J=7.3 Hz, 4.33 (2H, q, J=7.1 Hz), 2.49(2H, t, J=7.3 Hz), 2.31 (2H, q, J=7.3 Hz), 1.66 (3H, s), 1.60 (3H, s),1.35 (3H, t, J=7.1 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 202.83, 166.39,162.08, 133.42, 121.90, 101.64, 62.40, 40.92, 25.59, 23.34, 17.61, 13.96ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 25.59, 17.62, 13.97; CH₂carbons: 62.40, 40.92, 23.34; CH carbons: 121.90, 101.64 ppm. HPLC:11.007 min.

Synthesis of 5-(4-Methylpent-3-enyl)-1H-pyrazole-3-carboxylic acid ethylester (50)

Hydrazine hydrate (0.41 mL, 8.48 mmol) was added to a stirring roomtemperature solution of 49 (0.1.9190 g, 8.48 mmol) in EtOH (8.5 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC (½ h): The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 96:4 Hexanes:2N NH₃ in EtOH): ¹H(CDCl₃, 400 MHz): δ 12.73 (1H, broad s), 6.57 (1H, s), 5.09 (1H, t,J=6.8 Hz), 4.32 (2H, q, J=7.1 Hz), 2.70 (2H, t, J=7.5 Hz), 2.29 (2H, q,J=7.5 Hz), 1.63 (3H, s), 1.52 (3H, s), 1.30 (3H, t, J=7.1 Hz) ppm.Partial ¹³C (CDCl₃, 100 MHz): δ 162.27, 106.11, 60.65, 31.49, 27.53,25.52, 17.51, 13.10 ppm. HPLC: 9.986 min.

Synthesis of 5-(4-Methylpent-3-enyl)-1H-pyrazole-3-carboxylic acid (51)

Freshly prepared aq. NaOH (10 M in H₂O, 11.85 mmol) was added to astirring, room temperature solution of 50 (0.0.5269 g, 2.37 mmol) inMeOH (5.9 L, 0.4 M) under N₂. The reaction was then heated to refluxuntil the reaction was judged complete by HPLC (5 min): The reaction wasconcentrated, redissolved in H₂O, and extracted with EtOAc. 10% aq. HClwas added dropwise to the aqueous layer until the pH=2. The white solidthat precipitated from the reaction was filtered off and washed withcold H₂O. The solid was dried under vacuum overnight to obtain 0.4034 g(87.6%) of 51. ¹H (CD₃OD, 400 MHz): δ 6.56 (1H, s), 5.14 (1H, t), 2.68(2H, t, J=7.3 Hz), 2.33 (2H, q, J=7.3 Hz), 1.67 (3H, s), 1.56 (3H, s)ppm. ¹³C (CD₃OD, 100 MHz): δ 164.94, 148.55, 143.23, 123.94, 107.32,28.89, 27.04, 25.85, 17.69 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons:25.85, 17.69; CH₂ carbons: 28.89, 27.04; CH carbons: 123.94, 107.32 ppm:HPLC: 8.475 min.

Example 17 Synthesis of5-[2-(2,2,6-trimethylcyclohexyl)-ethyl]-1H-pyrazole-3-carboxylic acid(54)

Synthesis of 2,4-dioxo-6-(2,2,6-trimethylcyclohexyl)-hexanoic acid ethylester (52)

Sodium hydride (0.6447 g, 25.52 mmol) was added slowly to a NaCl icebath containing EtOH (10 mL, 2.6 M) stirring under N₂.4-(2,2,6-trimethylcyclohexyl)-butan-2-one (5.0072 g, 25.50 mmol) anddiethyloxalate (3.7241 g, 25.48 mmol) were mixed together, and thenadded to the chilled NaOEt solution. After stirring for 5 minutes, thereaction was warmed to room temperature. The reaction quicklysolidified. An additional 10 mL EtOH was added, and the reaction wasallowed to stand for another 3 h. The reaction was quenched at 0° C.with 1N HCl and extracted 2× with CH₂Cl₂. The combined organics werewashed with H₂O, dried with Na₂SO₄, filtered, concentrated, and purifiedby silica gel chromatography (Combiflash column, 1:1 Hexanes:CH₂Cl₂):Only pure fractions were combined and concentrated to obtain 52. ¹H(CDCl₃, 400 MHz): δ 14.51 (1H, broad s), 6.34 (1H, s), 4.34 (2H, q,J=7.1 Hz), 2.44(2H, t, J=8.3 Hz), 1.96-1.84(11H, m), 1.68-1.22 (m), 1.36(3H, t, J=7.1 Hz), 1.18-0.98 (m), 0.94 (3H, s), 0.87 (3H, s), 0.85 (3H,d, J=7.3 Hz) ppm. Partial ¹³C (CDCl₃, 100 MHz): δ 203.45, 167.17,162.40, 101.80, 62.71, 49.28, 42.60, 30.46, 20.86, 14.27 ppm. PartialDEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.27; CH₂ carbons: 62.71; CHcarbons: 101.80 ppm. HPLC: 12.576 min.

Synthesis of5-[2-(2,2,6-trimethylcyclohexyl)-ethyl]-1H-pyrazole-3-carboxylic acidethyl ester (53)

1Hydrazine hydrate (0.867 mL, 17.9mmol) was added to a stirring roomtemperature solution of 52 (5.2981 g, 17.9 mmol) in EtOH (17.9 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC. The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 97:3 Hexanes:2N NH₃ in EtOH) toobtain 1.6604 g (31.8%) of 53. Partial ¹H (CDCl₃, 400 MHz): δ 12.45 (1H,broad s), 6.58 (1H, s), 4.32 (2H, q, J=7.1 Hz), 2.63 (2H, t, J=8.3 Hz),1.31 (3H, t, J=7.1 Hz), 0.90 (3H, s), 0.83 (3H, s), 0.78 (3H, d, J=6.8Hz) ppm. Partial ¹³C (CDCl₃, 100 MHz): δ 106.04, 60.66, 48.99, 34.03,30.10, 24.89, 14.17 ppm. HPLC: 12.000 min.

Synthesis of5-[2-(2,2,6-trimethylcyclohexyl)-ethyl]-1H-pyrazole-3-carboxylic acid(54)

Freshly prepared aq. NaOH (10 M in H₂O, 2.73 mmol) was added to astirring, room temperature solution of 53 (0.1594 g, 0.5451 mmol) inMeOH (1.36 mL, 0.4 M) under N₂. The reaction was then heated to refluxuntil the reaction was judged complete by HPLC (5 min). The reaction wasconcentrated, redissolved in H₂O, and extracted with EtOAc. 10% aq. HClwas added dropwise to the aqueous layer until the pH=2. The white solidthat precipitated from the reaction was filtered off and washed withcold H₂O. The solid was dried under vacuum overnight to obtain 0.0119 g(8.2%) of 54. An additional 0.0590 g (40.9%) of 54 was obtained,although slightly impure, from the EtOAc layer. ¹H (CD₃OD, 400 MHz): δ6.56 (1H, s), 2.64 (2H, t, J=7.8 Hz), 2.03-1.89 (1H, m), 1.69-1.53 (2H,m), 1.55-1.41 (2H, m), 1.39-1.27 (2H, m), 1.20-1.06 (3H, m), 0.97 (3H,s), 0.91 (3H, s), 0.86 (3H, d, J=6.8 Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ165.07, 149.02, 143.33, 107.26, 50.24, 37.04, 35.11, 31.58, 31.33,29.00, 28.87, 28.37, 26.30, 22.13, 18.90 ppm. DEPT (CD₃OD, 100 MHz): CH₃carbons: 29.00, 28.87, 18.90; CH₂ carbons: 37.04. 31.33, 28.37, 26.30,22.13; CH carbons: 107.26, 50.24, 31.58 ppm. HPLC: 10.497 min.

Example 18 Synthesis of 5-(2-Phenylpropyl)-1H-pyrazole-3-carboxylic acid(58)

Synthesis of 4-Phenylpentan-2-one (55)

1.6 M Methyl lithium (22.8 mL, 36.5 mmol) was added over 1 hour to astirring 0° C. solution of 3-Phenylbutyric acid (1.8298 g, 11.14 mmol)in dry Et₂O (56 mL, 0.2 M): The ice bath was removed, and the reactionwas allowed to stir at room temperature for 2⅔ additional hours. Another0.8 mL MeLi (1.12 mmol, 0.10 equiv) was added, and the reaction wasstirred for another 30 minutes. The reaction was then poured intorapidly stirring ice water containing aq. HCl. The organic layer wasremoved, washed with NaHCO₃ and brine, then dried with Na₂SO₄, filteredand concentrated to achieve pure 55 (1.2324 g, 68.2%): ¹H (CDCl₃, 400MHz): δ 7.30 (2H, t, J=7.3 Hz), 7.22 (2H, d, J=7.3 Hz), 7.20 (2H, t,J=7.3 Hz), 3.37-3.27 (1H, m), 2.76 (1H, dd, J=16.1, 6.3 Hz), 2.66 (1H,dd, J=16.1, 7.8 Hz), 2.05 (3H, s), 1.28 (3H, d, J=7.3 Hz) ppm. ¹³C(CDCl₃, 100 MHz): δ 208.01, 146.42, 128.80, 127.03, 126.57, 52.16,35.67, 30.77, 22.28 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 30.77,22.28; CH₂ carbons: 52.16; CH carbons: 128.80, 127.03, 126.57, 35.67ppm. HPLC: 10.017 min. (Note: SM has HPLC retention time of 9.041 min.)

Synthesis of 2,4-dioxo-6-phenylheptanoic acid ethyl ester (56)

Sodium hydride (0.1702 g, 7.09 mmol) was added slowly to a NaCl ice bathcontaining EtOH (2.6 mL, 2.7 M) stirring under N₂. 4-Phenylpentan-2-one(55) (1.0493 g, 6.47 mmol) and diethyloxalate (0.88 mL, 6.47 mmol) weremixed together, and then added to the chilled NaOEt solution. Afterstirring for 5 minutes, the reaction was warmed to room temperature.After 90 min, the reaction was quenched at 0° C. with 1N HCl andextracted 2× with CH₂Cl₂. The combined organics were washed with H₂O,dried with Na₂SO₄, filtered, concentrated to provide 56 (0.7230 g,42.6%) which was used without further purification in the next step. ¹H(CDCl₃, 400 MHz): δ 7.34-7.16 (5H, m), 6.30 (1H, s), 4.33 (2H, q, J=7.0Hz), 3.39-3.26 (1H, m), 2.82 (1H, dd, J=15.1, 6.8 Hz), 2.72 (1H, dd,J=15.1, 7.8 Hz), 1.36 (3H, t, J=7.0 Hz), 1.32 (3H, d, J=6.8 Hz) ppm.HPLC: 10.934 min.

Synthesis of 5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid ethylester (57)

Hydrazine hydrate (0.134 mL, 2.76 mmol) was added to a stirring roomtemperature solution of 56 0.7230 g, 2.76 mmol) in EtOH (2.8 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC (50 min): The reaction was concentrated and purified bypreparative reverse phase HPLC with the following conditions: 0 to 24min, 55:45 H₂O:CH₃CN; 24-25 min, 55:45 to 0:100 H₂O: CH₃CN; 20 mL/min.;λ=214 nM; 100 mg/mL, 0.2 mL/injection. 0.0489 g of 57 was obtained. ¹H(CDCl₃, 300 MHz): δ 10.77 (1H, broad s), 7.36-7.14 (5H, m), 6.49 (1H,s), 4.33 (2H, q, J=7.0 Hz), 3.16-2.86 (3H, m), 1.33 (3H, t, J=7.0 Hz),1.27 (3H, d, J=5.9Hz) ppm. ¹³C (CDCl₃, 75 MHz): δ 162.01, 145.94,145.75, 141.50, 128.43, 126.76, 126.32, 106.98, 60.87, 39.94, 34.64,21.34, 14.12 ppm. DEPT (CDCl₃, 75 MHz): CH₃ carbons: 21.34, 14.12; CH₂carbons: 60.87, 34.64; CH carbons: 128.43, 126.77, 126.32, 106.98, 39.94ppm. HPLC: 10.052 min.

Synthesis of 5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid (58)

Freshly prepared aq. NaOH (10 M in H₂O, 0.947 mmol) was added to astirring, room temperature solution of 57 (0.0489 g, 0.1893 mmol) inMeOH (0.47 mL, 0.4 M) under N₂. The reaction was then heated to refluxuntil the reaction was judged complete by HPLC (8 min): The reaction wasconcentrated, redissolved in H₂ 0, and extracted with EtOAc (1 mL): 10%aq. HCl was added dropwise to the aqueous layer until the pH=2. Thewhite solid that precipitated from the reaction was filtered off andwashed with cold H₂O. The solid was dried under vacuum overnight toobtain 0.0298 g (68.3%) of 58. ¹H (CD₃OD, 400 MHz): δ 7.24 (2H, t, J=7.3Hz), 7.18 (2H, d, J=7.3 Hz), 7.14 (1H, t, J=7.3 Hz), 6.42 (1H, s),3.11-3.01 (1H, m), 2.95 (1H, dd, J=14.1, 7.3 Hz), 2.89 (1H, dd, J=14.1,7.8 Hz), 1.26 (3H, d, J=6.8 Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ 164.83,147.35, 147.13, 143.02, 129.45, 127.92, 127.35, 108.07, 41.46, 35.58,22.05 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons: 22.05; CH₂ carbons:35.58; CH carbons: 129.45, 127.92, 127.35, 108.07, 41.46 ppm. HPLC:8.764 min.

Example 19 Synthesis of5-(1-methyl-2-phenylethyl)-1H-pyrazole-3-carboxylic acid (62)

Synthesis of 3-Methyl-4-phenylbutan-2-one (59)

1.4 M Methyl lithium (34.8 mL, 48.72 mmol) was added over 70 min to astirring 0° C. solution of α-methylhydrocinnamic acid (4.0019 g, 24.36mmol) in dry Et₂O (122 mL, 0.2 M): The ice bath was removed, and thereaction was allowed to stir at room temperature for 2 additional hours.The reaction was the poured into rapidly stirring ice water containingaq. HCl. The organic layer was removed, washed with NaHCO₃ and brine,then dried with Na₂SO₄, filtered, concentrated, and purified by silicagel chromatography (Combiflash column, 95:5 Hexanes:EtOAc) to achievepure 59 (2.3038 g, 58.3%): ¹H (CDCl₃, 400 MHz): δ 7.28 (2H, t, J=7.3Hz), 7.20 (1H, t, J=7.3 Hz), 7.16 (2H, d, J=7.3 Hz), 3.00 (1H, dd,J=13.7, 6.8 Hz), 2.83 (1H, app sex, 7.0 Hz), 2.56 (1H, dd, J=13.7, 7.8Hz), 2.08 (3H, s), 1.09 (3H, d, J=6.8 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ211.99, 139.53, 128.79, 128.28, 126.10, 48.65, 38.75, 28.74, 16.10 ppm.DEPT (CDCl₃, 100 MHz): CH₃ carbons: 28.74, 16.10; CH₂ carbons: 38.75; CHcarbons: 128.79, 128.28, 126.10, 48.65 ppm. HPLC: 10.229 min. (Note: SMhas HPLC retention time of 9.225 min.)

Synthesis of5-methyl-2,4-dioxo-6-phenylhexanoic acid ethyl ester (60)

Sodium hydride (0.3965 g, 16.52 mmol) was added slowly to a NaCl icebath containing EtOH (5.6 mL, 2.6 M) stirring under N₂. 59 (2.2727 g,14.01 mmol) and diethyloxalate (2.0649 g, 14.13 mmol) were mixedtogether, and then added to the chilled NaOEt solution. After stirringfor 5 minutes, the reaction was warmed to room temperature. Afterstirring for 5 h, the reaction was quenched at 0° C. with 1N HCl andextracted 2× with CH₂Cl₂. The combined organics were washed with H₂O,dried with Na₂SO₄, filtered, concentrated, and purified by silica gelchromatography (Combiflash column, 67:30:3 Hexanes:CH₂Cl₂:2N NH₃ inEtOH): Only pure fractions were combined and concentrated to obtain 60.¹H (CDCl₃, 400 MHz): δ 14.55 (1H, broad s), 7.32-7.12 (5H, m), 6.36 (1H,s), 4.33 (2H, q, J=7.0 Hz), 3.05 (1H, dd, J=13.5, 6.8 Hz), 2.84 (1H, appsex, J=7.0 Hz), 2.67 (1H, dd, J=13.5, 7.8 Hz), 1.36 (3H, t, J=7.1 Hz),2.33 (3H, d, J=7.0 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 205.78, 166.96,161.88, 138.75, 128.80, 128.30, 126.29, 100.75, 62.32, 46.35, 39.10,16.51, 13.88 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 16.51, 13.88; CH₂carbons: 62.32, 39.10; CH carbons: 128.80, 128.30, 126.29, 100.75, 46.35ppm. HPLC: 11.084 min.

Synthesis of 5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid ethylester (61)

Hydrazine hydrate (0.1564 mL, 3.23 mmol) was added to a stirring roomtemperature solution of 60 (0.8460 g, 3.223 mmol) in EtOH (3.2 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC. The reaction was concentrated and purified by silica gelchromatography (Combiflash column, 87:7:4 Hexanes:CH₂Cl₂:2N NH₃ in EtOH)to obtain 0.6423 g (77.1%) of 61. ¹H (CDCl₃, 300 MHz): δ 7.26-7.14 (3H,m), 7.08 (2H, d, J=7.0 Hz), 6.61 (1H, s), 4.34 (2H, q, J=7.2 Hz), 3.23(1H, app sex, J=7.1 Hz), 3.00 (1H, dd, J=13.5, 6.7 Hz), 2.77 (1H, dd,J=13.5, 8.0 Hz), 1.34 (3H, t, J=7.1 Hz), 1.26 (3H, d, J=7.3 Hz) ppm.Partial ¹³C (CDCl₃, 75 MHz): δ 161.86, 139.47, 128.99, 128.20, 126.14,104.99, 60.80, 43.37, 33.39, 19.60, 14.18 ppm. DEPT (CDCl₃, 75 MHz): CH₃carbons: 19.60, 14.18; CH₂ carbons: 60.80, 43.37; CH carbons: 128.99,128.20, 126.14, 104.99, 33.39 ppm. HPLC: 10.129 min.

Synthesis of 5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid (62)

Freshly prepared aq. NaOH (10 M in H₂O, 1.01 mmol) was added to astirring, room temperature solution of 61 (0.0523 g, 0.2024 mmol) inMeOH (0.51 mL, 0.4 M) under N₂. The reaction was then heated to refluxuntil the reaction was judged complete by HPLC (9 min): The reaction wasconcentrated, redissolved in H₂O, and extracted with EtOAc. 10% aq. HClwas added dropwise to the aqueous layer until the pH=2. When a whitesolid did not precipitate as expected, EtOAc was added, and the organiclayer was removed, dried with Na₂SO₄, filtered, and concentrated toprovide pure 62. ¹H (CD₃OD, 400 MHz): δ 7.24-7.18 (2H, m), 7.17-7.05(3H, m), 6.56 (1H, s), 3.17 (1H, app sex, J=7.3 Hz), 2.96 (1H, dd,J=13.6, 7.3 Hz), 2.80 (1H, dd, J=13.7, 7.8 Hz), 1.25 (3H, d, J=6.8 Hz)ppm. ¹³C (CD₃OD, 100 MHz): δ 164.88, 153.40, 142.91, 140.97, 130.09,129.25, 127.21, 106.11, 44.41, 34.96, 20.35 ppm. DEPT (CD₃OD, 100 MHz):CH₃ carbon: 20.35; CH₂ carbon: 44.41; CH carbons: 130.09, 129.25,127.21, 106.11, 34.96 ppm. HPLC: 8.849 min.

Example 20 Synthesis of4-[2-(2-bromophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (65)

Synthesis of 4-[2-(2-bromophenyl)-acetyl]-1H-pyrrole-2-carboxylic acidethyl ester (63)

Ethylpyrrole-2-carboxylate (1.9428 g, 13.96 mmol) in a minimal amount(˜5 mL) of dichloroethane was added to an ice cooled stirring mixture ofaluminum chloride (4.0458 g, 30.34 mmol) and 2-bromophenylacetylchloride (6.7116 g, 28.74 mmol) in dichloroethane (44 mL, 0.66 M) underN₂. The ice bath was removed, and the reaction was stirred at roomtemperature for 2 h. 19.2977 g (2.6 mMol/g) Polyamine resin HL (200-400mesh) and dichloroethane (20 mL) were added, and the reaction wasstirred for ˜100 min. The reaction was then filtered through aglass-fritted funnel directly into ice water. The resin was rinsed withCH₂Cl₂, then the organic layers were removed, dried with Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography(Combiflash column, 80:20 to 60:40 Hexanes:EtOAc) to obtain 2.5751 g(54.9%) 63 as a white solid. Note: A small amount of CH₂Cl₂ was requiredto solubilize the crude product before placement on the silica column.¹H (CDCl₃, 400 MHz): δ 10.32 (1H, broad s), 7.57-7.53 (2H, m), 7.38-7.37(1H, m), 7.29-7.21 (2H, m), 7.13-7.07 (1H, m), 4.35 (2H, q, J=7.2 Hz),4.25 (2H, s), 1.36 (3H, t, J=7.2 Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ191.78, 161.04, 134.91, 132.62, 131.66, 128.59, 127.40, 126.95, 126.25,124.98, 124.17, 114.88, 60.92, 46.56, 14.26 ppm. DEPT (CDCl₃, 100 MHz):CH₃ carbons: 14.26; CH₂ carbons: 60.92, 46.56; CH carbons: 132.62,131.66, 128.59, 127.40, 126.95, 114.88 ppm. HPLC: 10.078 min.

Synthesis of 4-[2-(2-bromophenyl)-ethyl]-1H-pyrrole-2-carboxylic acidethyl ester (64)

Triethylsilane (2.25 mL, 14.1 mmol) was added to a stirring, roomtemperature solution of 63 (1.5291 g, 4.55 mmol) in trifluoroacetic acid(TFA) (10.8 mL, 0.42 M) under N₂. After stirring at room temperature for3 hours, the reaction was heated to 35° C. for 35 min, then the TFA wasremoved under vacuum, and the crude product was taken up in EtOAc,washed with brine, dried with Na₂SO₄, filtered, concentrated, andpurified by preparative reverse phase HPLC with the followingconditions: 0 to 12 min, 35:65 H₂O:CH₃CN; 14-15 min, 35:65 to 0: 100H₂O:CH₃CN; 20 mL/min.; λ=254 nM; 3.67 g/mL, 0.2 mL/ injection. 0.8402 g(57.3%) of 64 was obtained as a fluffy white solid. (Note: An undesiredimpurity has a retention time of 12.281 min by HPLC.) ¹H (CDCl₃, 400MHz): δ 9.07 (1H, broad s), 7.55 (1H, dd, J=8.0, 1.3 Hz), 7.21 (1H, td,J=7.3, 1.3 Hz), 7.17 (1H, dd, J=7.6, 2.4 Hz), 7.06 (1H, ddd, J=7.9, 7.0,2.3 Hz), 6.82 (1H, s), 6.72 (1H, s), 4.32 (2H, t, J=7.2 Hz), 2.99 (2H,t, J=8.0 Hz), 2.78 (2H, t, J=7.9Hz), 1.36 (3H, t, J=7.2 Hz) ppm. ¹³C(CDCl₃, 100 MHz): δ 161.21, 141.03, 132.75, 130.41, 127.63, 127.32,125.31, 124.43, 122.66, 120.68, 114.83, 60.22, 37.78, 27.03, 14.48 ppm.DEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.48; CH₂ carbons: 60.22, 37.78,27.03; CH carbons: 132.75, 130.41, 127.63, 127.32, 120.68, 114.83 ppm.HPLC: 11.355 min.

Synthesis of 4-[2-(2-bromophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid(65)

Freshly prepared aq. NaOH (10 M in H₂O, 13.04 mmol) was added to astirring, room temperature solution of 64 (0.8402 g, 2.608 mmol) in MeOH(6.5 mL, 0.4 M) under N₂. The reaction was heated to reflux until thereaction was judged complete by HPLC (10 min): The product wasconcentrated and then dissolved in 10 mL H₂O. The product was extractedwith EtOAc until the organic layer no longer turned yellow, then theaqueous layer was made acidic (pH=2) with the dropwise addition of 10%aq. HCl. The product oiled out of solution, so EtOAc was added, and theorganic layer was removed, dried with Na₂SO₄, filter, concentrated toobtain 65 (0.3934 g, 51.3%) as a white solid (Note: An undesiredimpurity has a retention time of 11.066 min by HPLC): ¹H (CD₃OD, 400MHz): δ 7.51 (1H, d, J=7.8 Hz), 7.24-7.16 (2H, m), 7.05 (1H, ddd, J=8.2,6.3, 2.9Hz), 6.72 (1H, s), 6.71 (1H, s), 2.96 (2H, t, J=8.0 Hz), 2.73(2H, t, J=7.8 Hz)) ppm. ¹³C (CD₃OD, 100 MHz): δ 164.48, 142.42, 133.71,131.80, 128.79, 128.53, 125.89, 125.20, 123.54, 122.61, 116.38, 38.99,28.20 ppm. DEPT (CDCl₃, 100 MHz): CH₂ carbons: 38.99, 28.20; CH carbons:133.71, 131.80, 128.79, 128.53, 122.61, 116.38 ppm. HPLC: 10.035 min.

Example 21 Synthesis of5-[2-(4-Chlorophenyl)-ethyl]-1H-pyrazole-3-carboxylic acid (69)

Synthesis of 4-(4-chlorophenyl)-butan-2-one (66)

1.6 M Methyl lithium (33.9 mL, 54.17 mmol) was added over 70 min to astirring 0° C. solution of 3-(4-chlorophenyl)-propionic acid (5.0072 g,27.08 mmol) in dry Et₂O (135 mL, 0.2 M): The ice bath was removed, andthe reaction was allowed to stir at room temperature overnight. Thereaction was the poured into rapidly stirring ice water containing aq.HCl. The organic layer was removed, washed with NaHCO₃ and brine, thendried with Na₂SO₄, filtered, concentrated, and purified by silica gelchromatography (Combiflash column, 98:2 to 95:5 Hexanes:EtOAc) toachieve pure 66 (2.4253 g, 49.0%): ¹H (CDCl₃, 400 MHz): δ 7.14 (2H, d,J=8.3 Hz), 7.03 (2H, d, J=8.3 Hz), 2.77 (2H, t, J=7.5 Hz), 2.64 (2H, t,J=7.5 Hz), 2.04 (3H, s) ppm. ¹³C (CDCl₃, 100 MHz): δ 207.12, 139.38,131.59, 129.55, 128.35, 44.62, 29.82, 28.78 ppm. DEPT (CDCl₃, 100 MHz):CH₃ carbons: 29.82; CH₂ carbons: 44.62, 28.78; CH carbons: 129.55,128.35 ppm. HPLC: 10.361 min. (Note: SM has HPLC retention time of 9.409min.)

Synthesis of 6(4-chlorophenyl)-2,4-dioxohexanoic acid ethyl ester (67)

Sodium hydride (0.4163 g, 17.35 mmol) was added slowly to a NaCl icebath containing EtOH (5.3 mL, 2.5 M) stirring under N₂. 66 (2.4253 g,13.28 mmol) and diethyloxalate (1.803 g, 13.28 mmol) were mixedtogether, and then added to the chilled NaOEt solution. After stirringfor 5 minutes, the reaction was warmed to room temperature. After 10minutes, the reaction solidified and an additional 10 mL EtOH was added.After stirring for 5 h, the reaction was quenched at 0° C. with 1N HCland extracted 2× with CH₂Cl₂. The combined organics were washed withH₂O, dried with Na₂SO₄, filtered, concentrated, and purified by silicagel chromatography (Combiflash column, 1:1 Hexanes:CH₂Cl₂): Only purefractions were combined and concentrated to obtain 67 (1.7561 g, 46.8%):¹H (CDCl₃, 400 MHz): δ 14.27 (1H, broad s), 7.22 (2H, d, J=8.3 Hz), 7.10(2H, d, J=8.3 Hz), 6.32 (1H, s), 4.31 (2H, q, J=7.2 Hz), 2.92 (2H, t,J=7.8 Hz), 2.78 (2H, t, J=7.8 Hz), 1.34 (3H, t, J=7.2 Hz) ppm. ¹³C(CDCl₃, 100 MHz): δ 201.59, 166.07, 161.79, 138.51, 132.00, 128.53,128.54, 101.72, 62.38, 42.08, 29.60, 13.88 ppm. DEPT (CDCl₃, 100 MHz):CH₃ carbons: 13.88; CH₂ carbons: 62.38, 42.08, 29.60; CH carbons:129.53, 128.54, 101.72ppm. HPLC: 11.103 min.

Synthesis of 5-[2-(4-Chlorophenyl)-ethyl]-1H-pyrazole-3-carboxylic acidethyl ester (68)

Hydrazine hydrate (0.300 mL, 6.18 mmol) was added to a stirring roomtemperature solution of 67 (0.1.7484 g, 6.18 mmol) in EtOH (6.2 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC (40 min): Upon cooling, a white crystalline solid precipitatedfrom the reaction. The solid was separated by filtration, washed withEtOH, and dried to obtain pure 68 (0.9092 g, 52.7%): ¹H (CDCl₃, 300MHz): δ 12.44 (1H, broad s), 7.21 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.1Hz), 6.58 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.00 (2H, t, J=7.0 Hz), 2.93(2H, t, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz) ppm. Partial ¹³C (CDCl₃, 75MHz): δ 139.12, 131.93, 129.67, 128.50, 106.49, 60.94, 34.72, 14.20 ppm.HPLC: 10.269 min.

Synthesis of 5-[2-(4-Chlorophenyl)-ethyl]-1H-pyrazole-3-carboxylic acid(69)

Freshly prepared aq. NaOH (10 M in H₂O, 16.31 mmol) was added to astirring, room temperature solution of 68 (0.9092 g, 3.26 mmol) in MeOH(8.2 mL, 0.4 M) under N₂. The reaction was then heated to reflux untilthe reaction was judged complete by HPLC (7 min). The reaction wasconcentrated, redissolved in H₂O (5 mL), and extracted with EtOAc (2mL). 10% aq. HCl was added dropwise to the aqueous layer until the pH=2.The white solid that precipitated was filtered off and washed with coldH₂O. The solid was dried under vacuum overnight to obtain 0.7543 g(92.2%) of 69. Since 69 still contained a very small amount of animpurity, it was dissolved in 38 mL of toluene with 10 mL of EtOAc and14 mL of EtOH while heating to reflux. Pure white solid precipitatedfrom the reaction after sitting overnight (0.4052 g). solid (Note: Anundesired impurity has a retention time of 9.904 min by HPLC). ¹H(CD₃OD, 400 MHz): δ 7.24 (2H, d, J=8.3 Hz), 7.15 (2H, d, J=8.3 Hz), 6.54(1H, s), 2.95 (4H, s) ppm. ¹³C (CD₃OD, 100 MHz): δ 164.68, 148.23,142.84, 140.91, 133.00, 131.08, 129.46, 107.59, 35.83, 28.78 ppm. DEPT(CD₃OD, 100 MHz): CH₂ carbons: 35.83, 28.78; CH carbons: 131.08, 129.46,107.59 ppm. HPLC: 9.026 min.

Example 22 Synthesis of5-bromo-4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (70)

Synthesis of5-bromo-4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (70)

Bromine (0.049 mL, 0.962 mmol) was added dropwise over 5 minutes to astirring solution of 39 (0.200 g, 0.802 mmol) in acetic acid (2.5 mL).When the reaction was judged complete by HPLC (30 min), H₂O was added,and the solid that precipitated was filtered off and washed with H₂O.The light purple solid that was obtained was dissolved in EtOAc, washedwith Na₂SO₃ and H₂O, then dried with Na₂SO₄, filtered, and concentrated.The product was purified by preparative reverse phase HPLC with 40:60H₂O:CH₃CN (w/0.05% TFA); 20 mL/min.; λ=214 nM. 0.1520 g.(57.7%) of 70was obtained as a fluffy white solid. ¹H (CD₃OD, 400 MHz): δ 7.22 (2H,d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.65 (1H, s), 2.81 (2H, t, J=7.3Hz), 2.67 (2H, t, J=7.3 Hz) ppm. Partial ¹³C (CD₃OD, 100 MHz): δ 163.33,141.42, 132.54, 131.03, 129.18, 124.73, 117.15, 105.84, 36.72, 29.04ppm. DEPT (CD₃OD, 100 MHz): CH₂ carbons: 36.72, 29.04; CH carbons:131.03, 129.18, 117.15 ppm. HPLC: 10.484 min.

Example 23 Synthesis of4-[2-(2-bromophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (73)

Synthesis of 4-[2-(4-fluorophenyl)-acetyl]-1H-pyrrole-2-carboxylic acidethyl ester (71)

Ethylpyrrole-2-carboxylate (2.0589 g, 14.80 mmol) in a minimal amount ofdichloroethane was added to an ice cooled stirring mixture of aluminumchloride (3.9913 g, 29.93 mmol) and 4-fluorophenylacetyl chloride(5.1338 g, 29.75 mmol) in dichloroethane (22 mL, 0.66 M) under N₂. Theice bath was removed, and the reaction was stirred at room temperaturefor 3.5 h. 20.6195 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) anddichloroethane (20 mL) were added, and the reaction was stirred for ˜60min. The reaction was then filtered through a glass-fritted funneldirectly into ice water. The resin was rinsed with CH₂Cl₂, then theorganic layers were removed, dried with Na₂SO₄, filtered andconcentrated. When 6.5 mL of 80:20 Hexanes:EtOAc were added, the organicliquid turned yellow, leaving behind a tan solid. The solid was removedby filtration, rinsed with 80:20 Hexanes:EtOAc, and dried to obtain pure71 (2.1838 g, 53.6%). ¹H (CDCl₃, 400 MHz): δ 10.03 (1H, broad s), 7.54(1H, s), 7.32 (1H, s), 7.23 (2H, dd, J=8.6, 5.3 Hz), 6.99 (2H, t, J=8.6Hz), 4.35 (2H, q, J=7.1 Hz), 4.04 (2H, s), 1.37 (3H, t, J=7.1 Hz) ppm.¹³C (CDCl₃, 100 MHz): δ 192.81, 161.84 (d, J=244 Hz), 160.95, 130.89 (d,J=7.8 Hz), 130.37 (d, J=3.2 Hz), 126.72, 126.36, 124.30, 115.40 (d,J=21.4 Hz), 114.96, 61.02, 45.63, 14.29 ppm. DEPT (CDCl₃, 100 MHz): CH₃carbons: 14.29; CH₂ carbons: 61.02, 45.63; CH carbons: 130.89 (d, J=7.8Hz), 126.72, 115.40 (d, J=21.4 Hz), 114.96 ppm. HPLC: 9.689 min.

Synthesis of 4-[2-(4-fluorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acidethyl ester (72)

Triethylsilane (3.84 mL, 24.1 mmol) was added to a stirring, roomtemperature solution of 71 (2.1400 g, 7.77 mmol) in trifluoroacetic acid(TFA) (18.5 mL, 0.42 M) under N₂. When the reaction was judged completeby HPLC, the TFA was removed under vacuum, and the crude product wastaken up in EtOAc, washed with brine, dried with Na₂SO₄, filtered,concentrated, and purified by preparative reverse phase HPLC with thefollowing conditions: 0 to 12 min, 35:65 H₂O:CH₃CN; 14-15 min, 35:65 to0:100 H₂O: CH₃CN; 20 mL/min.; λ=254 nM; 3.67 g/mL, 0.2 mL/injection.1.1571 g (57.0%) of 72 was obtained as a fluffy white solid. (Note: Anundesired impurity has a retention time of 11.414 min by HPLC.) ¹H(CDCl₃, 400 MHz): δ 9.33 (1H, broad s), 7.13 (2H, dd, J=8.5, 5.6 Hz),6.96 (2H, t, J=8.8 Hz), 6.79 (1H, s), 6.66 (1H, s), 4.33 (2H, t, J=7.1Hz), 2.86 (2H, t, J=7.1 Hz), 2.77 (2H, t, J=7.1 Hz), 1.36 (3H, t, J=7.1Hz) ppm. ¹³C (CDCl₃, 100 MHz): δ 161.31, 161.22 (d, J=242 Hz), 137.46(d, J=3.2 Hz), 129.71 (d, J=7.7 Hz), 125.22, 122.52, 120.84, 114.89 (d,J=21.9 Hz), 114.79, 60.19, 36.44, 28.73, 14.37 ppm. DEPT (CDCl₃, 100MHz): CH₃ carbons: 14.37; CH₂ carbons: 60.19, 36.44, 28.73; CH carbons:129.71 (d, J=7.7 Hz), 120.84, 114.89 (d, J=21.9 Hz), 114.79 ppm. HPLC:10.797 min.

Synthesis of 4-[2-(4-fluorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid(73)

Freshly prepared aq. NaOH (10 M in H₂O, 22.14 mmol) was added to astirring, room temperature solution of 72 (1.1571 g, 4.428 mmol) in MeOH(11.1 mL, 0.4 M) under N₂. The reaction was heated to reflux until thereaction was judged complete by HPLC (10 min). Upon cooling, thereaction solidified. The product was concentrated and then dissolved inH₂O. The product was extracted with EtOAc, then the aqueous layer wasmade acidic (pH=2) with the dropwise addition of 10% aq. HCl. Theproduct oiled out of solution, so EtOAc was added, and the organic layerwas removed, dried with Na₂SO₄, filter, concentrated to obtain 73(0.8724 g, 84.4%) as an off-white solid. The product was furtherpurified by repeating the above procedure. The product was dissolved in10% NaOH, washed with EtOAc, and then acidified with 10% HCl. As before,the product oiled out and was therefore extracted into EtOAc, dried withNa₂SO₄, filtered, and concentrated. ¹H (CD₃OD, 400 MHz): 7.14 (2H, dd,J=8.8, 5.4 Hz), 6.94 (2H, t, J=8.8 Hz), 6.68 (1H, d, J=1.7Hz), 6.66 (1H,d, J=7.1 Hz), 2.82 (2H, t, J=7.3 Hz), 2.72 (2H, t, J=7.3 Hz) ppm. ¹³C(CD₃OD, 100 MHz): δ 164.48, 162.69 (d, J=241 Hz), 139.28 (d, J=3.2 Hz),131.08 (d, J=8.2 Hz), 126.08, 123.47, 122.68, 116.41, 115.68 (d, J=21.0Hz), 37.77, 29.94 ppm. DEPT (CDCl₃, 100 MHz): CH₂ carbons: 37.77, 29.94;CH carbons: 131.08 (d, J=8.2 Hz), 122.68, 116.41, 115.68 (d, J=21.0 Hz)ppm. HPLC: 9.575 min.

Example 24 Synthesis of 4-(3-Cyclopentylpropyl)-1H-pyrrole-2-carboxylicacid (76)

Synthesis of 4-(3-Cyclopentylpropionyl)-1H-pyrrole-2-carboxylic acidethyl ester (74)

Ethylpyrrole-2-carboxylate (1.8593 g, 13.36 mmol) in a minimal amount ofdichloroethane was added to an ice cooled stirring mixture of aluminumchloride (3.5756 g, 26.82 mmol) and 3-cyclopentylpropionyl chloride (4.1mL, 26.59 mmol) in dichloroethane (20 mL, 0.66 M) under N₂. The ice bathwas removed, and the reaction was stirred at room temperature for 4 h.18.18 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) anddichloroethane (20 mL) were added, and the reaction was stirred for ˜60min. The reaction was then filtered through a glass-fritted funneldirectly into ice water. The resin was rinsed with CH₂Cl₂, then theorganic layers were removed, dried with Na₂SO₄, filtered andconcentrated. The crude product was recrystallized from Hexanes/Ethylacetate. The crude was dissolved in a minimal amount of hot EtOAc, thenallowed to slowly cool to room temperature. When no productcrystallized, a small amount of hexanes was pipetted down the sides ofthe flask. Pure crystals of desired product (2.3068 g, 65.6%) wereobtained after sitting overnight. ¹H (CDCl₃, 400 MHz): δ 10.04 (1H,broad s), 7.55 (1H, s), 7.29 (1H, s), 4.34 (2H, q, J=7.1 Hz), 2.77 (2H,t, J=7.6 Hz), 1.85-1.67 (5H, m), 1.64-1.46 (4H, m), 1.36 (3H, t, J=7.1Hz), 1.78-1.06 (2H, m) ppm. ¹³C (CDCl₃, 100 MHz): δ 196.38, 161.09,127.03, 126.14, 124.05, 114.76, 60.91, 39.82, 39.06, 32.53, 30.82,25.11, 14.31 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons: 14.31; CH₂carbons: 60.91, 39.06, 32.53, 30.82, 25.1 1; CH carbons: 126.14, 114.76,39.82 ppm. HPLC: 10.800 min.

Synthesis of 4-(3-cyclopentylpropyl)-1H-pyrrole-2-carboxylic acid ethylester (75)

Triethylsilane (4.28 mL, 26.86 mmol) was added to a stirring, roomtemperature solution of 74 (2.2816 g, 8.66 mmol) in trifluoroacetic acid(TFA) (20.6 mL, 0.42 M) under N₂. When the reaction was judged completeby HPLC, the TFA was removed under vacuum, and the crude product wastaken up in EtOAc, washed with brine, dried with Na₂SO₄, filtered,concentrated, and purified by preparative reverse phase HPLC with thefollowing conditions: 30:70 H₂O:CH₃CN; 20 mL/min.; λ=254 nm. 75 wasobtained as a fluffy white solid. ¹H (CDCl₃, 400 MHz): δ 9.43 (1H, broads), 6.77 (1H, s), 6.74 (1H, s), 4.32 (2H, q, J=7.1 Hz), 2.46 (2H, t,J=7.6 Hz),1.83-1.71 (3H, m), 1.64-1.46 (6H, m), 1.35 (3H, t, J=7.1 Hz),1.36-1.31 (2H, m), 1.14-1.02 (2H, m) ppm. ¹³C (CDCl₃, 100 MHz): δ161.46, 126.62, 122.33, 120.74, 114.86, 60.10, 40.00, 35.82, 32.65,30.14, 26.94, 25.13, 14.39 ppm. DEPT (CDCl₃, 100 MHz): CH₃ carbons:14.39; CH₂ carbons: 60.10, 35.82, 32.65, 30.14, 26.94, 25.13; CHcarbons: 120.74, 114.86, 40.00ppm. HPLC: 12.379min.

Synthesis of 4-(3-cyclopentylpropyl)1H-pyrrole-2-carboxylic acid (76)

Freshly prepared aq. NaOH (10 M in H₂O, 11.23 mmol) was added to astirring, room temperature solution of 75 (0.56 g, 2.25 mmol) in MeOH(5.6 mL, 0.4 M) under N₂. The reaction was heated to reflux until thereaction was judged complete by HPLC (10 min). Upon cooling, thereaction solidified. The product was concentrated and H₂O was added.When the product would not dissolve in H₂O, EtOAc was added, followed by10% HCl to acidify the aqueous layer. The organic was then removed,dried with Na₂SO₄, filtered, concentrated, and purified by preparativereverse phase HPLC with the following conditions: 30:70 H₂O:CH₃CN; 20mL/min.; λ=254 nm. 76 was obtained as a fluffy white solid. (Note: Anundesired impurity has a retention time of 12.073 min by HPLC). ¹H(CD₃OD, 400 MHz): δ 10.80 (1H, s), 6.72 (1H, s), 6.68 (1H, s), 2.43 (2H,t, J=7.6 Hz), 1.82-1.70 (3H, m), 1.64-1.46 (6H, m), 1.38-1.29 (2H),1.14-1.02 (2H, m) ppm. ¹³C (CD₃OD, 100 MHz): δ 164.45, 127.29, 122.45,116.39, 41.31, 37.00, 33.73, 31.43, 27.96, 26.11 ppm. DEPT (CDCl₃, 100MHz): CH₂ carbons: 37.00, 33.73, 31.43, 27.96, 26.11; CH carbons:122.45, 116.39, 41.31 ppm. HPLC: 10.977 min.

Example 25 Synthesis of (S)-5-(2-Phenylpropyl)-1H-pyrazole-3-carboxylicacid (80)

Synthesis of (S)-4-Phenylpentan-2-one (77)

1.6 M Methyl lithium (17.8 mL, 24.9 mmol) was added over 1 hour to astirring 0° C. solution of (S)-3-Phenylbutyric acid (2.0147 g, 12.18mmol) in dry Et₂O (61 mL, 0.2 M): The ice bath was removed, and thereaction was allowed to stir at room temperature for 1½ additionalhours. The reaction was then poured into rapidly stirring ice watercontaining aq. HCl. The organic layer was removed, washed with NaHCO₃and brine, then dried with Na₂SO₄, filtered and concentrated to achievepure 77 (2.0487 g, (2.0487 g,˜100%): HPLC: 10.081 min. (Note: SM hasHPLC retention time of 9.127 min.)

Synthesis of (S)-2,4-dioxo-6-phenylheptanoic acid ethyl ester (78)

Sodium hydride (0.3790 g, 15.8 mmol) was added slowly to a NaCl ice bathcontaining EtOH (4.9 mL, 2.5 M) stirring under N₂.(S)4-Phenylpentan-2-one (78) (2.0487 g, 12.63 mmol) and diethyloxalate(1.67 mL, 12.30 mmol) were mixed together, and then added to the chilledNaOEt solution. After stirring for 5 minutes, the reaction was warmed toroom temperature. After 60 min, the reaction was quenched at 0° C. with1N HCl and extracted 2× with CH₂Cl₂. The combined organics were washedwith H₂O, dried with Na₂SO₄, filtered, concentrated, and purified with1:1 to 1:3 Hexanes:CH₂Cl₂ to obtain 78 (0.6895 g, 20.8%): HPLC: 10.940min.

Synthesis of (S)-5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid ethylester (79)

Hydrazine hydrate (0.126 mL, 2.59 mmol) was added to a stirring roomtemperature solution of 78 0.0.6895 g, 2.63 mmol) in EtOH (2.6 mL, 1 M)under N₂. The reaction was then heated to reflux until judged completeby HPLC (45 min): The reaction was concentrated and purified with 9:1 to8:1 Hexanes:(3:1 CH₂Cl₂:2N NH₃ in EtOH) to achieve 0.6153 g (90.6%) of79. HPLC: 10.001 min.

Synthesis of (S)-5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid (80)

Freshly prepared aq. NaOH (10 M in H₂O, 11.9 mmol) was added to astirring, room temperature solution of 79 (0.6153 g, 0.2.38 mmol) inMeOH (6 mL, 0.4 M) under N₂. The reaction was then heated to refluxuntil the reaction was judged complete by HPLC (7 min): The reaction wasconcentrated, redissolved in H₂O, and extracted with EtOAc (1 mL): 10%aq. HCl was added dropwise to the aqueous layer until the pH=2. Thewhite solid that precipitated from the reaction was filtered off andwashed with cold H₂O. The solid was dried under vacuum overnight toobtain 0.250 g (45.6%) of 80. ¹H (CD₃OD, 400 MHz): δ 7.30-7.23 (2H, m),7.22-7.13 (3H, m), 6.62 (1H, s), 3.14 (1H, app sex, J=7.3 Hz), 3.03 (2H,d, J=7.8 Hz), 1.31 (3H, d, J=6.8 Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ162.00, 149.20, 146.35, 141.76, 129.62, 127.93, 127.64, 109.16, 41.21,35.22, 22.11 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons: 22.11; CH₂carbons: 35.22; CH carbons: 129.62, 127.93, 127.64, 109.16, 41.21 ppm.HPLC: 8.771 min.

Analytical HPLC conditions: Reverse phase analytical column. At time=0,95:5 H₂O:CH3CN; ramp up to 60:40 H₂O:CH₃CN by 4 min;

Example 26 In Vitro Measurements of DAAO activity

Purified pig DAAO, added to a buffered mixture of 50 mM D-Serineproduces H₂O₂ in stoichiometric amounts for each D-Serine moleculeoxidized. H₂O₂ production can be monitored with a commercially availabledye Amplex Red, which in the presence of H₂O₂, is converted to thefluorescent product resorufin. For each described inhibitor, thefluorescence was also measured during additions of 80 μM H₂O₂ in theabsence of DAAO, to control for artifactual inhibition of the dyeconversion, and to quantify the amount of H₂O₂ produced. In analternative assay of DAAO activity, the purified pig DAAO is added tobuffered mixture of 1 mM phenylglycine in the presence of compounds. Theactivity of DAAO is monitored spectrophotometrically by its enzymaticconversion of phenylglycine to benzoylformic acid with opticalabsorption at 252 nm.

Inhibitors of DAAO's enzymatic cycle were serially diluted to reduce thelevel of inhibition. The parameters of a non-linear equation wereadjusted to fit the resulting series of inhibition levels to extrapolatethe concentration of compound where 50% inhibition is achieved (IC₅₀).These numbers are averaged for the number (n) of independentmeasurements (on separate days) of the inhibition. The inhibition isreported in Table 1. TABLE1 Compound No. Inhibition of Compound No.Inhibition of or Structure DAAO, IC₅₀ or Structure DAAO, IC₅₀  3  <10 μM45 <100 μM  6  <10 μM 48  <10 μM 11 + 12  <10 μM 51  <1 μM 15  <10 μM 54<100 μM 18  <1 μM 58  <1 μM 21  <1 μM 62  <1 μM 24  <1 μM 65  <1 μM 26<100 μM 69  <1 μM 32 >100 μM 70 <100 nM 36 <100 μM 73  <1 μM 39  <1 μM76  <10 μM 42  <1 μM 80  <10 μM

 <1 μM

<100 μM

 <1 μM

<100 μM

 <1 μM

<100 μM

 <1 μM

<100 μM

 <1 μM

<100 μM

 <1 μM

<100 μM

 <10 μM

<100 μM

 <10 μM

<100 μM

 <10 μM

<100 μM

 <10 μM

<100 μM

 <10 μM

<100 μM

 <10 μM

<100 μM

 <10 μM

>100 μM

 <10 μM

>100 μM

 <10 μM

It can be seen from Table 1 that the IC₅₀ values of previously reportedDAAO inhibitors are all greater than 1 μM compound for greater than 50%inhibition of DAAO activity. The pyrrole and pyrazole derivatives of thepresent invention display at least this much inhibitory activity, andseveral individual examples are 5-fold or greater more active, requiringless than 200 nM of the compounds to inhibit 50% of DAAO activity.

Example 27 Measurements of NMDA Receptor Affinity

To measure the affinity of the compounds reported herein for D-Serine'sbinding site on the NMDA receptor (also known as the “Glycine site” orthe “strychnine-insensitive glycine site”), a radioligand-binding assaywas performed with membranes prepared from rat cerebral cortex. Theradioactive ligand was [3H]MDL105,519. The amount of radioactivitydisplaced by the compounds was assessed by scintillation counting.Non-specific binding is accounted for in the presence of 1 mM Glycine.Affinities are calculated from the values of % inhibition of specific[3H]MDL105,519 binding by the test compounds.

Indole-2-carboxylic acid inhibited 77% of specific binding of theradiolabeled compound when tested at 100 μM, while the followingcompounds, exemplary of substituted pyrroles and pyrazoles, demonstratedno affinity (less than 20% inhibition of [3H]MDL-509,519 specificbinding when tested at 100 μM) for the D-Serine binding site of the NMDAreceptor:

Example 28 Measurements of Rat Brain Uptake

Experiments that evaluate the rat brain penetration of test compoundsuse a perfusion system where the left carotid artery is cannulated andthe branch arteries are tied off. The test compound plus internalcontrols are perfused for 30 seconds into the left hemisphere inphosphate buffered saline at pH 7.4. The internal controls are atenolol(with low brain uptake) and antipyrine (with high brain uptake). After a30 second washout with perfusate, the brain is removed surgically. Theleft hemisphere is homogenized; test compounds (plus internal controls)are extracted from brain homogenate, and analyzed using LC/MS/MS todetermine the concentration of test compound and internal controls inthe brain. Brain uptake rates for selected compounds, expressed aspmol/g brain/sec±SD for N of 4 rats, are shown in Table 2. TABLE 2Compound No. (from Examples) Rat Brain Uptake Rate, or Structure pmol/gbrain/sec 18 17 21 6 39 204

6

Example 29 Measurements of Brain D-Serine Levels

Measurements of d-serine in the brains of mammals indicate that thelevel of endogenous production is balanced by degradation of d-serine.D-serine is produced from l-serine by the action of serine racemase,while d-serine is metabolized by the action of DAAO. Exogenouslyadministered d-serine produces short lasting increases in brain d-serinedue to the action of DAAO. Likewise, inhibitors of DAAO are shown inthis invention to increase several-fold brain levels of d-serine. Theclinical utility of exogenously-administered d-serine has beendemonstrated in schizophrenics; see Coyle, Joseph J., Ann. NAY. AcadSci., 1003: 318-327 (2003) and U.S. Pat. Nos. 6,227,875; 6,420,351; and6,667,297. Therefore, measurements of brain d-serine levels in rats areuseful for assessing the potential therapeutic action of DAAO inhibitorson increases in d-serine for the treatment of schizophrenia.

In vivo increase in brain D-Serine Compounds were suspended in phosphatebuffered saline (pH 7.4 with 2% Tween80) and were administeredintraperitoneally into adult male Sprague Daly rats (40-60 days old,Charles River Laboratories, Inc.) weighing 185-225 g at the time of theexperiment. After several hours, the rats were killed by decapitationand the cerebellum was rapidly removed and frozen to −80C for furtheranalysis. The remainder of the brain was likewise removed and frozen. Onthe day of the analysis, the brain tissue was homogenized in 5 times itsvolume in ice-cold 5% trichloroacetic acid. The homogenate wascentrifuged at 18,000 times gravity for 30 minutes. Pellets werediscarded. The supernatant was washed 3 times with water-saturateddiethyl ether, discarding the organic layer. After filtration of theaqueous layer through a 0.45 μm pore size filter membrane, the sampleswere ready for derivatization with o-phthaldialdehyde (OPA) and BOCL-Cys-OH according to the methods of Hashimoto and colleagues (HashimotoA, et al., J Chromatogr., 582(1-2):41-8 (1992)). Briefly, 50 mg of eachderivatization reagent were dissolved in 5 ml of methanol. A 200 μlaliquot of this was added to 100 μl of sample dissolved in 700 μl ofborate buffer (0.4 M pH adjusted to 9.0 with sodium hydroxide). D-Serinelevels were then detected fluorometrically (344 nm excitationwavelength, 443 nm emission wavelength) by injecting 10 μl aliquots intothe high-performance liquid chromotography system.

Compounds exemplary of those in this patent produced robust andsignificant increases in D-Serine levels in rat brain. In particular, apyrrole derivative administered in two separate doses (125 mg/kgfollowed by 75 mg/kg 3 hours later) produced a 4-fold increase incerebellar D-Serine levels 6 hours after the first dose.

Example 30 Reduction of Neuropathic Pain by DAAO Inhibitors in AnimalModel (Spinal Nerve Ligation (SNL) Model)

Animals: Male Sprague-Dawley rats (Hsd:Sprague-Dawley®™SD®™, Harlan,Indianapolis, Ind., U.S.A.) weighing 232±2 g the day of behavioraltesting were housed three per cage. Animals had free access to food andwater and were maintained on a 12:12 h light/dark schedule for theentire duration of the study. The animal colony was maintained at 21° C.and 60% humidity. All experiments were conducted in accordance with theInternational Association for the Study of Pain guidelines and hadAnimal Care and Use Committee approval.

Induction of chronic neuropathic pain: The Spinal Nerve Ligation (SNL)model (Kim and Chung, 1992) was used to induce chronic neuropathic pain.The animals were anesthetized with isoflurane, the left L5 transverseprocess was removed, and the L5 and L6 spinal nerves were tightlyligated with 6-0 silk suture. The wound was then closed with internalsutures and external staples. Wound clips were removed 10-11 daysfollowing surgery.

Mechanical allodynia testing: Baseline, post-injury and post-treatmentvalues for non-noxious mechanical sensitivity were evaluated using 8Semmes-Weinstein filaments (Stoelting, Wood Dale, Ill., USA) withvarying stiffness (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, and 15 g)according to the up-down method (Chaplan et al., 1994). Animals wereplaced on a perforated metallic platform and allowed to acclimate totheir surroundings for a minimum of 30 minutes before testing. The meanand standard error of the mean (SEM) were determined for each animal ineach treatment group. Since this stimulus is normally not consideredpainful, significant injury-induced increases in responsiveness in thistest are interpreted as a measure of mechanical allodynia.

Experimental Groups: Dose vol. of (mg/ adm. Time course # SurgeryTreatment kg) Route Vehicle (ml/kg) (hours) n 1 SNL4-[2-(4-chlorophenyl)- 125 i.p. PBS 2 BL, 2, 4, 6, 8 10ethyl]-1H-pyrrole-2- carboxylic acid (39) 1 SNL Gabapentin 100 i.p.saline 5 BL, 0.5, 1, 2, 4 10 3 SNL saline — i.p. — 2 BL, 2, 4, 6, 8  9Timeline:4-[2-(4-Chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (39) and(vehicle)(1) von Frey test (baseline)(2) 0 min: drug administration(3) 120 min: von Frey test(4) 240 min: von Frey test(5) 360 min: von Frey test(6) 480 min: von Frey test(7) 495 min: plasma collection

Blinding procedure: Drugs were administered by a separate experimenterthat was not involved with conducting the behavioral testing. The blindwas not broken until the end of the study.

Data analysis: Statistical analyses were conducted using Prism™ 4.01(GraphPad, San Diego, Calif., USA). Mechanical hypersensitivity of theinjured paw was determined by comparing contralateral to ipsilateral pawvalues within the vehicle group. Data were analyzed using theMann-Whitney test. Stability of vehicle group injured paw values overtime was tested using the Friedman two-way analysis of variance by rank.Drug effect was analyzed at each time point by carrying out aKruskal-Wallis one-way analysis of variance by rank followed by a Dunn'spost hoc test or Mann-Whitney signed rank test.

Results: 4-[2-(4-Chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acidinduced a substantial decrease in mechanical allodynia that wasstatistically significant at 240 and 360 min. The maximum effect wasobserved 360 minutes post dose.

References:

-   Chaplan S R, Bach F W, Pogrel J W, Chung J M and Yaksh T L (1994)    Quantitative assessment of tactile allodynia in the rat paw. J    Neurosci Methods 53:55-63.-   Kim S H and Chung J M (1992) An experimental model for peripheral    neuropathy produced by segmental spinal nerve ligation in the rat.    Pain 50:355-63.

Example 31 Dosage Forms Lactose-Free Tablet Dosage Form

Table 3 provides the ingredients for a lactose-free tablet dosage formof a compound of formula I: TABLE 3 Quantity per Ingredient Tablet (mg)5-phenethyl-1H-pyrazole-3-carboxylic acid 75 Microcrystalline cellulose125 Talc 5.0 Water (per thousand tablets) 30.0 mL* Magnesium Stearate0.5*The water evaporates during manufacture.

The active ingredient is blended with the cellulose until a uniformblend is formed. The smaller quantity of cornstarch is blended with asuitable quantity of water to form a corn starch paste. This is thenmixed with the uniform blend until a uniform wet mass is formed. Theremaining cornstarch is added to the resulting wet mass and mixed untiluniform granules are obtained. The granules are then screened through asuitable milling machine, using a ¼ inch stainless steel screen. Themilled granules are then dried in a suitable drying oven until thedesired moisture content is obtained. The dried granules are then milledthrough a suitable milling machine using ¼ mesh stainless steel screen.The magnesium stearate is then blended and the resulting mixture iscompressed into tablets of desired shape, thickness, hardness anddisintegration. Tablets are coated by standard aqueous or nonaqueoustechnique.

Tablet Dosage Form

Another tablet dosage formulation suitable for use with the activeingredients of the invention is provided in Table 4. TABLE 4 Quantityper Tablet (mg) Ingredient Formula A Formula B Formula C5-phenethyl-1H-pyrazole-3- 20 40 100 carboxylic acid Microcrystallinecellulose 134.5 114.5 309.0 Starch BP 30 30 60 Pregelatinized MaizeStarch BP 15 15 30 Magnesium Stearate 0.5 0.5 1.0 Compression Weight 200200 500

The active ingredient is sieved and blended with cellulose, starch andpregelatinized maize starch. Suitable volumes of purified water areadded and the powders are granulated. After drying, the granules arescreened and blended with the magnesium stearate. The granules are thencompressed into tablets using punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to pharmaceutically acceptable carrier, thecompression weight, or by using different punches.

Example 32 Synthesis of4-[2-(4-Chloro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (87)

ynthesis of (Toluene-4-sulfonylamino)-acetic acid ethyl ester (81)

Tosyl chloride (14.75 g, 77.37 mmol) was added to a stirring mixture ofglycine ethyl ester hydrochloride (9.0 g, 64.48 mmol) and pyridine(11.45 mL, 141.85 mmol) in 100 mL of dichloromethane. After stirringovernight, the mixture was washed with water and dilute NaOH. Thecombined organics were dried with Na₂SO₄, filtered, evaporated underreduced pressure to give 16.0 g (96%) of 81, which was used withoutpurification in the next reaction. ¹H-NMR (400 MHz, CDCl₃): δ 1.18 (t,3H), 2.42 (s, 3H), 3.76 (d, 2H), 4.08 (q, 2H), 5.22 (m, 1H), 7.30 (d,2H), 7.75 (d, 2H) ppm. ¹³C-NMR (100 MHz), CDCl₃): δ 13.99, 21.55, 44.19,61.89, 127.28, 129.76, 136.20, 143.81, 168.87 ppm. DEPT (100 MHz,CDCl₃): CH₃ carbons: 13.99, 21.55; CH₂ carbons: 44.19, 61.89; CHcarbons: 127.28, 129.76 ppm. LC/MS: 95%, m/z=257.

Synthesis of3-Hydroxy-3-methyl-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acidethyl ester (82)

1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (7 mL, 47.08 mmol) was addedto a stirred solution of ethyl vinyl ketone (1.75 mL, 21.4 mmol) andethyl N-p-toluenesulfonylglycinate 81 (5.5 g, 21.4 mL) in THF (50 mL).The resulting mixture was stirred overnight at room temperature. Themixture was diluted with ether, washed with 5% aq. HCl, 5% sodiumbicarbonate solution and water. The combined organics were dried withNa₂SO₄, filtered, evaporated under reduced pressure to give crude 82(5.3 g, 76%) as a yellow oil (diastereoisomers mixture). ¹H-NMR (400MHz, CDCl₃): δ 1.29 (m, 6H), 1.75 (m, 1H), 2.09 (m, 1H), 2.43 (s, 3H),3.40 (m, 1H), 3.56 (m, 1H), 4.04 (s, 1H), 4.20 (m, 2H), 7.30 (d, 2H),7.75 (d, 2H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 14.12, 15.28, 23.04,25.60, 26.27, 38.20, 38.86, 46.26, 46.46, 61.49, 61.65, 69.10, 71.69,127.51, 129.70, 134.83, 134.91, 143.58, 143.84, 170.03, 170.45 ppm. DEPT(100 MHz, CDCl₃): CH₃ carbons: 14.12, 15.28, 23.04, 25.60, 26.27; CH₂carbons: 38.20, 38.86, 46.26, 46.46, 61.49, 61.65; CH carbons: 69.10,71.69, 127.51, 129.70 ppm.

LC/MS: 97.60%, m/z=327.

Synthesis of3-Methyl-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acidethyl ester (83)

The pyrrolidine oil 82 (10.5 g, 32.11 mmol) was dissolved in pyridine(86 mL). POCl₃ (7.48 mL, 80.27 mmol) was added dropwise and theresulting mixture stirred overnight at room temperature. The mixture waspoured over ice, extracted with ether and washed with 5% aq. HCl, 5%sodium bicarbonate solution and water. The ether layer was dried oversodium sulfate, filtered and evaporated under reduced pressure to givethe crude solid 83 (8.80 g, 88%). ¹H-NMR (400 MHz, CDCl₃): δ 1.28 (t,3H), 1.69 (m, 3H), 2.43 (s, 3H), 4.10 (m, 1H), 4.20 (q, 2H), 4.21 (m,1H), 7.31 (d, 2H), 7.75 (d, 2H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 13.58,14.10, 21.56, 54.64, 61.62, 70.55, 110.02, 122.51, 127.51, 129.73,169.87 ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons: 13.58, 14.10, 21.56; CH₂carbons: 54.64, 61.62; CH carbons: 70.55, 122.51, 127.51, 129.73 ppm.LC/MS: 100%, m/z=309.

Synthesis of 3-Methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84)

Pyrroline 83 (8.80 g, 28.48 mmol) was dissolved in THF (70 mL). DBU(9.78 mL, 65.50 mmol) was added dropwise and the resulting solutionstirred under reflux overnight. The mixture was cooled to roomtemperature, diluted with ether and washed with 5% aq. HCl, 5% sodiumbicarbonate solution and water. The organic layer was dried over sodiumsulfate, filtered and evaporated under reduced pressure to give thecrude solid 84 (4.30 g, 98%). ¹H-NMR (400 MHz, CDCl₃): δ 1.37 (t, 3H),2.35 (s, 3H), 4.31 (q, 2H), 6.08 (d, 1H), 6.81 (d, 1H), 8.90 (s broad,1H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 12.76, 14.53, 59.96, 112.58,119.35, 121.53, 127.96, 162.01 ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons:12.76, 14.53; CH₂ carbons: 59.96; CH carbons: 112.58, 121.53 ppm. LC/MS:90.74%, m/z=153.

Synthesis of4-[2-(4-Chloro-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (85)

A solution of (4-chlorophenyl)-acetyl chloride (3 mmol) indichloromethane or 1,2-dichloroethane (4 ml) was added to a solutioncooled at −40° C. of 84 (0.229 g, 1.5 mmol) and AlCl₃ was added (0.400g, 3 mmol). The reaction mixture was stirred for 30 minutes at the sametemperature. The reaction mixture was poured into ice-water andextracted with ethyl acetate. The organic layer was washed with NaOH (2M) and brine, dried over Na₂SO₄, and evaporated to dryness under vacuumto give crude product 85. Crude yield: 96%

¹H-NMR (400 MHz, CDCl₃): δ 1.37 (t, 3H), 2.60 (s, 3H), 4.00 (s, 2H),4.35 (q, 2H), 7.27 (m, 4H), 7.49 (d, 1H), 8.83 (s broad, 1H) ppm.¹³C-NMR (100 MHz, CDCl₃): δ 11.81, 14.38, 46.52, 60.94, 121.65, 124.57,127.46, 128.81, 130.81, 133.54, 162.13, 193.36 ppm. DEPT (100 MHz,CDCl₃): CH₃ carbons: 11.81, 14.38; CH₂ carbons: 46.52, 60.94; CHcarbons: 121.65, 128.81, 130.81 ppm. LC/MS: 90.32%, m/z=305.

Synthesis of4-[2-(4-Chloro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (86)

Triethylsilane (3 equivalents) was added to a solution of 85 intrifluoroacetic acid (2 mL per mmol). The mixture was stirred for 48 hat room temperature. The TFA was removed under vacuum and the crudeproduct was taken up in AcOEt, washed with NaOH (2 M), brine, dried withNa₂SO₄, filtered and concentrated to give crude product. The residue waspurified by HPLC. Yield: 46% for two steps. ¹H-NMR (400 MHz, CDCl₃): δ1.35 (t, 3H), 2.26 (s, 3H), 2.69 (m, 2H), 2.78 (m, 2H), 4.31 (q, 2H),6.55 (d, 1H), 7.08 (d, 2H), 7.22 (d, 2H), 8.86 (s broad, 1H) ppm.

Synthesis of4-[2-(4-Chloro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (87)

Freshly prepared aq. NaOH (1M in H₂O, 10 equivalents) was added at roomtemperature to a stirred solution of 86 (1 equivalent) in a mixture of1,4-dioxane and H₂O (v/v 3:1). The reaction was heated to 80° C. untilthe reaction was judged complete by TLC. The product was extracted withEt₂O, then the aqueous layer was made acid (pH=1) with the dropwiseaddition of 10% aq. HCl. The solid was filtered off and washed withwater. The solid was dried under vacuum overnight to obtain 87. Yield:66%. ¹H-NMR (400 MHz, CD₃OD): δ 2.19 (s, 3H), 2.69 (m, 2H), 2.78 (m,2H), 6.58 (d, 1H), 7.11 (d, 2H), 7.22 (d, 2H) ppm. LC/MS: 100%, m/z=263.HPLC (200-400 nm): 95.93%

Example 33 Synthesis of4-[2-(4-Methoxy-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid(90)

Synthesis of4-[2-(4-Methoxy-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (88)

4-[2-(4-Methoxy-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (88) was synthesized from 3-Methyl-1H-pyrrole-2-carboxylicacid ethyl ester (84) following the procedure described in Example 32.Crude yield: 97% ¹H-NMR (400 MHz, CDCl₃): δ 1.36 (t, 3H), 2.61 (s, 3H),3.79 (s, 3H), 3.97 (s, 2H), 4.33 (q, 2H), 6.50 (d, 2H), 7.16 (d, 2H),7.46 (d, 1H), 2.61 (s, 3H), ¹³C-NMR (100 MHz, CDCl₃): δ 11.75, 14.41,46.60, 55.27, 60.68, 114.07, 127.09, 130.43, 158.45, 194.19 ppm. DEPT(100 MHz, CDCl₃): CH₃ carbons: 11.75, 14.41, 55.27; CH₂ carbons: 46.60,60.68; CH carbons: 114.07, 127.09, 130.43 ppm. LC/MS: 76.86%, m/z=301.

Synthesis of4-[2-(4-Methoxy-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (89)

4-[2-(4-Methoxy-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (89) was synthesized from4-[2-(4-Methoxy-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (88) following the procedure described in Example 32. Yield:23% ¹H-NMR (400 MHz, CDCl₃): δ 1.36 (t, 3H), 2.27 (s, 3H), 2.69 (m, 2H),2.76 (m, 2H), 3.79 (s, 3H), 4.31 (q, 2H), 6.59 (d, 1H), 6.82 (m, 2H),7.08 (m, 2H), 8.70 (s broad, 1H) ppm.

¹³C-NMR (100 MHz, CDCl₃): δ 10.23, 14.56, 27.34, 35.78, 55.27, 59.85,113.70, 119.69, 129.35, 134.14, 157.81 ppm. DEPT (100 MHz, CDCl₃): CH₃carbons: 10.23, 14.56, 55.27; CH₂ carbons: 27.34, 35.78, 59.85; CHcarbons: 113.70, 119.69, 129.35, 134.14 ppm. LC/MS: 100%, m/z=287.

Synthesis of4-[2-(4-Methoxy-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid(93)

4-[2-(4-Methoxy-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid(93) was synthesized from4-[2-(4-Methoxy-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (92) following the procedure described in Example 32. Yield:66%. ¹H-NMR (400 MHz, CD₃OD): δ 6 2.19 (s, 3H), 2.65 (m, 2H), 2.72 (m,2H), 3.75 (s, 3H), 6.59 (d, 1H), 6.79 (m, 2H), 7.04 (m, 2H) ppm. ¹³C-NMR(100 MHz, CDCl₃): δ 10.46, 28.51, 37.32, 55.62, 114.64, 121.89, 125.45,127.46, 130.44, 135.54, 165.07 ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons:10.46, 55.62; CH₂ carbons: 28.51, 37.32; CH carbons: 114.64, 121.89,130.44 ppm. LC/MS: 100%, n/z=259. HPLC (200-400 nm): 94.17%.

Example 34 Synthesis of4-[2-(3-Methoxyphenyl)-ethyl7-3-methyl-1H-pyrrole-2-carboxylic acid (90)

Synthesis of4-[2-(3-Methoxy-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (91)

4-[2-(3-Methoxy-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (91) was synthesized from 3-methyl-1H-pyrrole-2-carboxylicacid ethyl ester (84) and (3-methoxyphenyl)-acetyl chloride followingthe procedure described in Example 32. crude yield: 95%. ¹H-NMR (400MHz, CDCl₃): δ 1.36 (t, 3H), 2.61 (s, 3H), 3.77 (s, 3H), 3.99 (s, 2H),4.32 (q, 2H), 6.81 (m, 3H), 7.24 (m, 1H), 7.45 (d, 1H), 9.41 (s broad,1H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 11.75, 14.40, 47.59, 55.19, 60.66,112.19, 115.04, 121.71, 127.22, 129.58, 136.75, 159.75, 193.65 ppm. DEPT(100 MHz, CDCl₃): CH₃ carbons: 11.75, 14.40, 55.19; CH₂ carbons: 47.59,60.66; CH carbons: 112.19, 115.04, 121.71, 127.22, 129.58 ppm. LC/MS:60.20%, m/z=301

Synthesis of4-[2-(3-Methoxyphenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (92)

4-[2-(3-Methoxyphenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (92) was synthesized from4-[2-(3-Methoxyphenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (91) following the procedure described in Example 32. Yield:18%. ¹H-NMR (400 MHz, CDCl₃): δ 1.36 (t, 3H), 2.28 (s, 3H), 2.72 (m,2H), 2.79 (m, 2H), 3.79 (s, 3H), 4.31 (q, 2H), 6.61 (d, 1H), 6.67 (m,3H), 7.20 (m, 1H), 8.72 (s broad, 1H) ppm.

¹³C-NMR (100 MHz, CDCl₃): δ 10.24, 14.56, 26.99, 36.73, 55.16, 59.87,111.11, 114.27, 119.65, 120.89, 129.28, 159.04 ppm. DEPT (100 MHz,CDCl₃): CH₃ carbons: 10.24, 14.56, 55.16; CH₂ carbons: 26.99, 36.73,59.87; CH carbons: 111.11, 114.27, 119.65, 120.89, 129.28 ppm. LC/MS:100%, m/z=287.

Synthesis of4-[2-(3-Methoxy-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid(93)

4-[2-(3-Methoxy-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid(93) was synthesized from4-[2-(3-Methoxyphenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (92) following the procedure described in Example 32. Yield:57%. ¹H-NMR (400 MHz, CD₃OD): δ 2.20 (s, 3H), 2.70 (m, 2H), 2.76 (m,2H), 3.73 (s, 3H), 6.61 (d, 1H), 6.72 (m, 3H), 7.13 (m, 1H) ppm. ¹³C-NMR(100 MHz, CDCl₃): □ 10.48, 28.18, 38.25, 55.51, 112.30, 115.17, 121.95,125.37, 130.18, 145.05, 161.10 ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons:10.48, 55.51; CH₂ carbons: 28.18, 38.25; CH carbons: 112.30, 115.17,121.95, 130.18 ppm. LC/MS: 93.45%, m/z=259. HPLC (200-400 nm): 69.03%.

Example 35 Synthesis of4-[2-(4-Fluoro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (96)

Synthesis of4-[2-(4-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (94)

4-[2-(4-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (94) was synthesized from 3-methyl-1H-pyrrole-2-carboxylicacid ethyl ester (84) and (4-fluorophenyl)-acetyl chloride following theprocedure described in Example 32. Crude yield: 94%. ¹H-NMR (400 MHz,CDCl₃): δ 1.36 (t, 3H), 2.61 (s, 3H), 4.01 (s, 2H), 4.35 (q, 2H), 7.01(m, 2H), 7.22 (m, 2H), 7.50 (d, 1H), 9.70 (s broad, 1H) ppm. ¹³C-NMR(100 MHz, CDCl₃): □ 11.79, 14.38, 46.36, 60.89, 115.51, 127.27, 129.93,130.77, 162.04, 193.62 ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons: 11.79,14.38; CH₂ carbons: 46.36, 60.89; CH carbons: 115.51, 127.27, 129.93,130.77 ppm. LC/MS: 77.48%, m/z=289.

Synthesis of4-[2-(4-fluorophenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethylester (95)

4-[2-(4-Fluorophenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethylester (95) was synthesized from4-[2-(4-fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (94) following the procedure described in Example 32. Yield:23%

¹H-NMR (400 MHz, CDCl₃): δ 1.36 (t, 3H), 2.26 (s, 3H), 2.69 (m, 2H),2.78 (m, 2H), 4.31 (q, 2H), 6.57 (d, 1H), 6.95 (m, 2H), 7.10 (m, 2H),8.70 (s broad, 1H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 10.21, 14.55, 27.20,35.90, 59.89, 114.89, 115.10, 119.70, 124.60, 129.77, 137.58, 160.00ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons: 10.21, 14.55; CH₂ carbons:27.20, 35.90, 59.89; CH carbons: 121.65, 128.81, 130.81 ppm. LC/MS:100%, m/z=275.

Synthesis of4-[2-(4-Fluoro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (96)

4-[2-(4-Fluorophenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (96)was synthesized from4-[2-(4-fluorophenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethylester (95) following the procedure described in Example 32. Yield: 22%.¹H-NMR (400 MHz, CDCl₃): δ 2.19 (s, 3H), 2.68 (m, 2H), 2.77 (m, 2H),6.58 (d, 1H), 6.95 (m, 2H), 7.12 (m, 2H) ppm. DEPT (100 MHz, CDCl₃): CH₃carbons: 10.43; CH₂ carbons: 28.32, 37.31; CH carbons: 115.61, 121.90,131.11 ppm. LC/MS: 100%, m/z=247. HPLC (200-400 nm): 98.44%.

Example 36 Synthesis of4-[2-(3-Fluorophenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (99)

Synthesis of4-2-(3-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethylester (97)

4-[2-(3-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (84) and (3-Fluorophenyl)-acetyl chloride following theprocedure described in Example 32. Crude yield: 93%. ¹H-NMR (400 MHz,CDCl₃): δ 1.37 (t, 3H), 2.61 (s, 3H), 4.03 (s, 2H), 4.35 (q, 2H), 7.00(m, 3H), 7.27 (m, 1H), 7.49 (d, 1H), 9.57 (s broad, 1H) ppm. ¹³C-NMR(100 MHz, CDCl₃): □ 11.76, 14.38, 46.93, 60.84, 113.64, 116.30, 125.13,127.17, 129.94, 137.42, 161.64, 193.02 ppm. DEPT (100 MHz, CDCl₃): CH₃carbons: 11.76, 14.38; CH₂ carbons: 46.93, 60.84; CH carbons: 116.30,125.13, 127.17, 129.94 ppm. LC/MS: 91.29%, m/z=289.

Synthesis of4-[2-(3-Fluoro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (98)

4-[2-(3-Fluoro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (98) was synthesized from4-[2-(3-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acidethyl ester (98) following the procedure described in Example 32. Yield:27%

¹H-NMR (400 MHz, CDCl₃): δ 1.36 (t, 3H), 2.27 (s, 3H), 2.72 (m, 2H),2.81 (m, 2H), 4.31 (q, 2H), 6.59 (d, 1H), 6.88 (m, 3H), 7.22 (m, 1H),8.79 (s broad, 1H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 10.22, 14.55, 26.80,36.43, 59.93, 112.64, 115.18, 119.72, 124.16, 129.72, 144.51, 161.65ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons: 10.22, 14.55; CH₂ carbons:26.80, 36.43, 59.93; CH carbons: 112.64, 115.18, 119.72, 124.16, 129.72ppm. LC/MS: 100%, m/z=275.

Synthesis of4-[2-(3-Fluoro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (99)

4-[2-(3-Fluoro-phenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (99)was synthesized from4-[2-(3-Fluorophenyl)-ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethylester (98) following the procedure described in Example 32. Yield: 55%.¹H-NMR (400 MHz, CDCl₃): δ 2.20 (s, 3H), 2.69 (m, 2H), 2.81 (m, 2H),6.61 (d, 1H), 6.87 (m, 2H), 6.95 (m, 1H), 7.24 (m, 1H) ppm. DEPT (100MHz, CDCl₃): CH₃ carbons: 10.43; CH₂ carbons: 27.95, 37.84; CH carbons:113.53, 116.27, 121.87, 125.48, 130.79 ppm. LC/MS: 100%, m/z=247. HPLC(200-400 nm): 80.81%.

Example 37 Synthesis of3-Methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (93)

Synthesis of3-methyl-4-[2-(4-trifluoromethylphenyl)-acetyl-1H-pyrrole-2-carboxylicacid ethyl ester (100)

3-Methyl-4-[2-(4-trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (100) was synthesized from3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and(4-trifluoromethylphenyl)-acetyl chloride following the proceduredescribed in Example 32. Crude yield: 96%. ¹H-NMR (400 MHz, CDCl₃): δ1.38 (t, 3H), 2.61 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.37 (m, 2H),7.51 (d, 1H), 7.58 (m, 2H), 9.29 (s broad, 1H) ppm. ¹³C-NMR (100 MHz,CDCl₃): δ 11.71, 14.41, 46.90, 60.78, 123.70, 124.70, 125.49, 126.75,129.41, 129.85, 130.00, 161.98, 193.49 ppm. DEPT (100 MHz, CDCl₃): CH₃carbons: 11.71, 14.41; CH₂ carbons: 46.90, 60.78; CH carbons: 123.70,124.70, 125.49, 126.75, 129.41, 129.85, 130.00 ppm. LC/MS: 73.23%,n/z=339.

Synthesis of3-methyl-4-[2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (101)

3-Methyl-4-[2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (101) was synthesized from3-methyl-4-[2-(4-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (100) following the procedure described in Example 32.Yield: 22%. ¹H-NMR (400 MHz, CDCl₃): δ 1.36 (t, 3H), 2.27 (s, 3H), 2.73(m, 2H), 2.87 (m, 2H), 4.31 (q, 2H), 6.56 (d, 1H), 7.26 (m, 2H), 7.52(m, 2H), 8.72 (s broad, 1H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 10.21,14.54, 26.78, 36.51, 59.95, 119.70, 124.23, 125.18, 128.81, 161.68 ppm.DEPT (100 MHz, CDCl₃): CH₃ carbons: 10.21, 14.54; CH₂ carbons: 26.78,36.51, 59.95; CH carbons: 119.70, 124.23, 125.18, 128.81 ppm.

LC/MS: 100%, m/z=325.

Synthesis of3-methyl-4-[2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (102)

3-Methyl-4-[2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (102) was synthesized from3-methyl-4-[2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (101) following the procedure described in Example 32.Yield: 60%. ¹H-NMR (400 MHz, CDCl₃): δ 2.20 (s, 3H), 2.73 (m, 2H), 2.89(m, 2H), 6.59 (d, 1H), 7.32 (m, 2H), 7.54 (m, 2H) ppm. ¹³C-NMR (100 MHz,CDCl₃): δ 10.42, 27.84, 37.90, 120.14, 121.92, 124.74, 126.04, 127.37,130.26, 148.11, 164.99 ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons: 10.42;CH₂ carbons: 27.84, 37.90; CH carbons: 121.92, 126.04, 130.27 ppm.LC/MS: 100%, m/z=297. HPLC (200-400 nm): 94.63%.

Example 38 Synthesis of3-Methyl-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (96)

Synthesis of3-Methyl-4-[2-(3-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (105)

3-Methyl-4-[2-(3 -trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (103) was synthesized from3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and(3-trifluoromethylphenyl)-acetyl chloride following the proceduredescribed in Example 32. Crude yield: 97%. ¹H-NMR (400 MHz, CDCl₃): δ1.38 (t, 3H), 2.62 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.45 (m, 2H),7.51 (m, 3H), 9.40 (s broad, 1H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 11.73,14.40, 46.73, 60.78, 123.70, 124.70, 126.82, 128.93, 129.71, 133.01,135.85, 161.61, 192.58 ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons: 11.73,14.40; CH₂ carbons: 46.73, 60.78; CH carbons: 123.70, 126.82, 128.93,129.71, 133.01 ppm. LC/MS: 79.18%, m/z=339.

Synthesis of3-Methyl-4-[2-(3-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (104)

3-Methyl-4-[2-(3 -trifluoromethylphenyl)-ethyl]-1H -pyrrole-2-carboxylicacid ethyl ester (104) was synthesized from3-methyl-4-[2-(3-trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (103) following the procedure described in Example 32.Yield: 16%. ¹H-NMR (400 MHz, CDCl₃): δ 1.36 (t, 3H), 2.26 (s, 3H), 2.74(m, 2H), 2.87 (m, 2H), 4.31 (q, 2H), 6.58 (d, 1H), 7.38 (m, 4H), 8.72 (sbroad, 1H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 10.20, 14.54, 26.87, 35.56,59.93, 119.67, 122.77, 124.25, 125.16, 128.67, 131.95, 142.77 ppm. DEPT(100 MHz, CDCl₃): CH₃ carbons: 10.20, 14.54; CH₂ carbons: 26.87, 35.56,59.93; CH carbons: 119.67, 122.77, 125.16, 128.67, 131.95 ppm. LC/MS:100%, m/z=325.

Synthesis of3-Methyl-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (105)

3-Methyl-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (105) was synthesized from3-methyl-4-[2-(3-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (104) following the procedure described in Example 32.¹H-NMR (400 MHz, CDCl₃): □ 2.18 (s, 3H), 2.73 (m, 2H), 2.89 (m, 2H),6.60 (d, 1H), 7.42 (m, 4H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ 10.39,27.93, 37.87, 121.93, 123.57, 124.69, 126.22, 127.40, 129.94, 133.52,144.72, 165.01 ppm. DEPT (100 MHz, CDCl₃): CH₃ carbons: 10.39; CH₂carbons: 27.93, 37.87; CH carbons: 121.93, 123.57, 126.22, 129.94,133.52 ppm. LC/MS: 100%, m/z=297. HPLC (200-400 nm): 96.89%.

Example 39 4-[2-(4-Chlorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylicacid (110)

Synthesis of 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107)

Sodium nitrite (1 1.5 g; 0.160 mol) in water (20 ml) was added dropwiseto an ice cooled stirring solution of ethyl acetoacetate (20.7 g; 0.159mol) in acetic acid (20 ml). The reaction temperature was maintainedbelow 10° C. The mixture was stirred for an additional 1 h at 5° C. andstored overnight at 0° C. to give oxime 97 as an orange-red solution.This solution was added to a mixture of acetoacetaldehyde dimethylacetal (21 g; 0.159 mol) and glacial acetic acid (35 ml), previouslywarmed to 60° C., and a mixture of zinc dust (30 g; 0.459 mol) andsodium acetate (30g; 0.364 mol) was simultaneously and slowly added.After the addition, the mixture was stirred for an additional 2 h. themixture was poured into ice-water (300 ml) to give a yellow precipitate.Filtration and recrystallization from methanol/water yielded 3.5 g (27%)of 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107), as acream-colored needles. ¹H (CDCl₃, 400 MHz): δ 9.10 (NH, broad s), 6.82(1H, d), 5.95 (1H, s), 4.29 (2H, q), 2.31 (3H, s), 1.35 (3H, t) ppm. ¹³C(CDCl₃, 100 MHz): δ 161.5, 134.1, 121.2, 116.1, 101.8, 60.1, 15.5, 13.1ppm. LC/MS: 97%.

Synthesis of4-[2-(4-Chlorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (108)

4-[2-(4-Chlorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (108) was synthesized from 5-methyl-1H-pyrrole-2-carboxylicacid ethyl ester (107) and (4-chlorophenyl)-acetyl chloride followingthe procedure described in Example 32. Reaction Conditions:1,2-dichloroethane/RT. Purification: recrystallization fromether/pentane. Yield: 83%. ¹H (CDCl₃, 400 MHz): δ 9.65 (NH, broad s),7.28 (3H, m), 7.2 (2H, d), 4.35 (2H, q), 4.04 (2H, s), 2.57 (3H, s),1.38 (3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 193.7, 161.5, 141.0, 133.5,132.6, 130.9, 130.7, 128.9, 128.6, 121.4, 120.5, 116.9, 61.0, 46.1,14.4, 14.0 ppm. LC/MS: 100%

Synthesis of4-[2-(4-Chlorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethylester (109)

4-[2-(4-Chlorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethylester (109) was synthesized from4-[2-(4-chlorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (108) following the procedure described in Example 32.Purification: Recrystallization from ether/pentane. Yield: 82%. ¹H(CDCl₃, 400 MHz): δ 9.65 (NH, broad s), 7.20 (2H, d), 7.04 (2H, d), 6.72(1H, s), 4.29 (2H, q), 2.78 (2H, dd), 2.64 (2H, dd), 2.04 (3H, s), 1.35(3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 161.6, 140.4, 131.5, 131.2, 129.9,128.3, 121.3, 119.8, 115.7, 60.1, 36.7, 27.8 14.5, 11.0 ppm. LC/MS: 96%.

Synthesis of4-[2-(4-Chlorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (110)

To a solution of4-[2-(4-Chlorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethylester (109) in dioxane, 10 equiv of NaOH aq (1.5 M) was added then themixture was heated at 80° C. for 3 hours. When the reaction is judgedcomplete, the solvent is removed under vacuum, H₂O was added and anequal volume of Et₂O was added. The organic layer was removed then theaqueous layer was made acidic with HCl (1M). If the product precipitatesout at this point, it was filtered off, washed with H₂O, and dried toobtain pure desired product. If the product didn't crash out when theaqueous layer is made acidic, Et₂O was added, and the organic layer wasremoved (2×). The organic layer was dried with Na₂SO₄, filtered, andconcentrated to obtain desired product. Purification: precipitation.Amount: 20.6 mg. ¹H (MeOD, 400 MHz): δ 7.2 (2H, dd), 7.08 (2H, dd), 6.59(1H, s), 2.76 (2H, dd), 2.63 (2H, dd), 1.97 (3H, s) ppm. DEPT (CD₃OD,100 MHz): CH₃: δ 10.8, CH₂: □ 28.9, 38.0, CH: 116.4, 129.1, 131.3 ppm.HPLC (20 min): 97.8%. LC/MS: 100%.

Example 40 Synthesis of4-[2-(4-Fluoro-phenyl)-ethyl7-5-methyl-1H-pyrrole-2-carboxylic acid(113)

Synthesis of4-[2-(4-Fluorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (111)

4-[2-(4-Fluorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (111) was synthesized from 5-methyl-1H-pyrrole-2-carboxylicacid ethyl ester (107) and (4-Fluorophenyl)-acetyl chloride followingthe procedure described in Example 32. Reaction Conditions:1,2-dichloroethane/RT. Purification: recrystallization fromether/pentane. Yield: 76%. ¹H (CDCl₃, 400 MHz): δ 10.5 (NH, broad s),7.31 (1H, s), 7.22 (2H, dd), 6.99 (2H, dd), 4.36 (2H, q), 4.06 (2H, s),2.58 (3H, s), 1.39 (3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 194.1, 163.0,161.5, 160.6, 141.0, 131.1, 130.7, 121.5, 120.5, 116.9, 115.4, 115.2,61.0, 45.9, 14.4, 14.0 ppm. LC/MS: 100%.

Synthesis of4-[2-(4-Fluoro-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (112)

4-[2-(4-Fluorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethylester (112) was synthesized from4-[2-(4-Fluoro-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (111) following the procedure described in Example 32.Purification: Recrystallization from ether/pentane. Yield: 86%. ¹H(CDCl₃, 400 MHz): δ 9.45 (NH, broad s), 7.06 (2H, m), 6.94 (2H, m), 6.72(1H, s), 4.29 (2H, q), 2.78 (2H, dd), 2.64 (2H, dd), 2.03 (3H, s), 1.34(3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 162.5, 160.1, 137.6, 131.1, 129.9,121.4, 119.8, 115.7, 115.0, 60.0, 36.5, 28.0 14.5, 11.0 ppm. LC/MS:100%.

Synthesis of4-[2-(4-Fluorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (113)

4-[2-(4-Fluorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (113)was synthesized from4-[2-(4-Fluoro-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (112) following the procedure described in Example 39.Purification: precipitation. Amount: 21.5 mg. ¹H (CD₃OD, 400 MHz): δ7.10 (2H, dd), 6.94 (2H, dd), 6.60 (1H, s), 2.77 (2H, dd), 2.64 (2H,dd), 1.97 (3H, s) ppm. ¹³C (CD₃OD, 100 MHz): δ 166.0, 161.5, 139.4,131.5, 131.3, 131.2, 122.5, 121.9, 116.6, 115.8, 115.5, 37.8, 29.1, 10.8ppm. HPLC (20 min): 96.6%. LC/MS: 100%.

Example 41 Synthesis of4-[2-(3-Fluoro-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid(116)

Synthesis of4-[2-(3-Fluoro-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (114)

4-[2-(3-Fluorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (114) was synthesized from 5-methyl-1H-pyrrole-2-carboxylicacid ethyl ester (107) and (3-fluorophenyl)-acetyl chloride followingthe procedure described in Example 32. Reaction Conditions:1,2-dichloroethane/RT. Purification: recrystallization fromether/pentane. Yield: 78%. ¹H (CDCl₃, 400 MHz): δ 10.6 (NH, broad s),7.30 (1H, s), 7.26 (1H, dd), 7.04 (1H, d), 6.99 (1H, d), 6.92 (1H, dd),4.37 (2H, q), 4.07 (2H, s), 2.58 (3H, s), 1.39 (3H, t) ppm. ¹³C (CDCl₃,100 MHz): δ 193.5, 164.0, 141.0, 137.4, 130.0, 125.3, 121.5, 120.5,116.9, 116.4, 113.7, 61.0, 46.4, 14.4, 14.0 ppm. LC/MS: 98%.

Synthesis of4-[2-(3-Fluorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethylester (115)

4-[2-(3-Fluorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethylester (115) was synthesized from4-[2-(3-Fluoro-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (114) following the procedure described in Example 32.Purification: Recrystallization from ether/pentane. Yield: 79%. ¹H(CDCl₃, 400 MHz): δ 9.55 (NH, broad s), 7.19 (1H, m), 6.86 (3H, m), 6.72(1H, s), 4.29 (2H, q), 2.80 (2H, dd), 2.66 (2H, dd), 2.07 (3H, s), 1.34(3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 164.1, 161.6, 144.6, 131.1, 129.7,124.2, 121.3, 119.8, 115.6, 115.2, 112.6, 60.1, 37.1, 27.6, 14.5, 11.0ppm. LC/MS: 93%.

Synthesis of4-[2-(3-Fluorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (116)

4-[2-(3-Fluorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (117)was synthesized from4-[2-(3-Fluorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethylester (116) following the procedure described in Example 39.Purification: Extraction. Amount: 10 mg. ¹H (MeOD, 400 MHz): δ 7.23 (1H,m), 6.94 (1H, d), 6.84 (2H, m), 6.65 (1H, s), 2.79 (2H, dd), 2.66 (2H,dd), 2.0 (3H, s) ppm. DEPT (MeOD, 100 MHz): CH₃: □ 10.8, CH₂: δ 28.7,38.3, CH: 113.3, 116.3, 117.4, 125.5, 130.7 ppm. HPLC (20 mn): 96.4%.LC/MS: 94%.

Example 42 Synthesis of5-Methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (119)

Synthesis of5-Methyl-4-[2-(4-trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (117)

5-Methyl-4-[2-(4-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (117) was synthesized from5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and(4-trifluoromethylphenyl)-acetyl chloride following the proceduredescribed in Example 32. Reaction Conditions: 1,2-dichloroethane/−40° C.Purification: prep/HPLC. Yield: 33%. ¹H (CDCl₃, 400 MHz): δ 10.5 (NH,broad s), 7.56 (2H, d), 7.34 (2H, d), 7.32 (1H, s), 4.37 (2H, q), 4.15(2H, s), 2.59 (3H, s), 1.38 (3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 193.3,161.5, 141.0, 139.0, 130.9, 125.5, 128.6, 121.4, 120.6, 114.0 61.0,46.5, 14.5, 14.0 ppm. LC/MS: 98%.

Synthesis of5-Methyl-4-[2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (118)

5-Methyl-4-[2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (118) was synthesized from5-methyl-4-[2-(4-trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (117) following the procedure described in Example 32.Purification: prep/HPLC. Yield: 50%. ¹H (CDCl₃, 400 MHz): δ 9.35 (NH,broad s), 7.50 (2H, d7.23 (2H, d), 6.72 (1H, s), 4.29 (2H, q), 2.85 (2H,dd), 2.66 (2H, dd), 2.03 (3H, s), 1.34 (3H, t) ppm. HPLC: 100%.Synthesis of5-Methyl-4-[2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (119)

5-Methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (119) was synthesized from5-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (118) following the procedure described in Example 39.Purification: Extraction. Amount: 11.6 mg. ¹H (CDCl₃, 400 MHz): δ 9.15(NH, broad s), 7.50 (2H, d), 7.24 (2H, d), 6.86 (1H, s), 2.89 (2H, dd),2.68 (2H, dd), 2.04 (3H, s) ppm. ¹³C (CDCl₃, 100 MHz): δ 165.7, 145.9,132.5, 128.4, 128.13, 125.2, 122.0, 118.8, 117.9, 37.0, 27.5, 11.2 ppm.HPLC (20 min): 94.5%. LC/MS: 97%.

Example 43 Synthesis of5-Methyl-4-[2-(3-trifuoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (122)

Synthesis of5-Methyl-4-[2-(3-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (120)

5-Methyl-4-[2-(3-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (120) was synthesized from5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and(3-trifluoromethylphenyl)-acetyl chloride following the proceduredescribed in Example 32. Reaction Conditions: 1,2-dichloroethane/−40° C.Purification: prep/HPLC. Yield: 16%. ¹H (CDCl₃, 400 MHz): δ 10.7 (NH,broad s), 7.48 (4H, m), 7.34 (1H, s), 4.37 (2H, q), 4.15 (2H, s), 2.59(3H, s), 1.39 (3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 193.3, 161.6, 141.2,136.0, 133.2, 131.2, 128.8, 128.2, 126.4, 123.6, 121.4, 120.6, 116.9,61.0, 46.3, 14.3, 13.9 ppm. LC/MS: 100%.

Synthesis of5-Methyl-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (121)

5-Methyl-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (121) was synthesized from5-Methyl-4-[2-(3-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylicacid ethyl ester (120) following the procedure described in Example 32.Purification: prep /HPLC. ¹H (CDCl₃, 400 MHz): δ 9.25 (NH, broad s), 7.4(4H, m), 6.72 (1 H, s), 4.30 (2H, q), 2.87 (2H, dd), 2.68 (2H, dd), 2.03(3H, s), 1.35 (3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 161.5, 142.8, 132.0,130.9, 130.7, 130.4, 128.7, 125.2, 122.7, 121.0, 120.0, 115.6, 60.1,37.2, 27.7, 14.5, 11.0 ppm. LC/MS: 94%.

Synthesis of5-Methyl-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (122)

5-Methyl-4-[2-(3 -trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (122) was synthesized from5-Methyl-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (121) following the procedure described in Example 39.Purification: Extraction. Amount: 9.5 mg. ¹H (CD₃OD, 400 MHz): δ 7.4(4H, m), 6.65 (1H, s), 2.87 (2H, dd), 2.69 (2H, dd), 1.95 (3H, s) ppm.¹³C (CD₃OD, 100 MHz): δ 164.5, 144.7, 133.6, 132.6, 131.3, 129.9, 126.3,123.6, 121.8, 121.0, 117.4, 38.3, 28.7, 10.7 ppm. HPLC (20 min): 95.6%.LC/MS: 100%.

Example 44 Synthesis of4-[2-(4-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid(125)

Synthesis of4-[2-(4-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (123)

4-[2-(4-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (123) was synthesized from 5-methyl-1H-pyrrole-2-carboxylicacid ethyl ester (107) and (4-Methoxyphenyl)-acetyl chloride followingthe procedure described in Example 32. Reaction Conditions:1,2-dichloroethane/ −40° C. Purification: prep/HPLC. Yield: 72%. ¹H(CDCl₃, 400 MHz): δ 10.45 (NH, broad s), 7.31 (1H, s), 7.18 (2H, d),6.84 (2H, d), 4.37 (2H, q), 4.01 (2H, s), 3.74 (3H, s), 2.57 (3H, s),1.38 (3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 194.7, 161.5, 158.4, 140.8,130.5, 127.1, 121.6, 120.4, 117.1, 114.0, 60.8, 55.2, 46.0, 14.4, 14.0ppm. LC/MS: 100%.

Synthesis of4-[2-(4-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (124)

4-[2-(4-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (124) was synthesized from4-[2-(4-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (123) following the procedure described in Example 32.Purification: Recrystallization from ether/pentane. Yield: 75%. ¹H(CDCl₃, 400 MHz): δ 9.0 (NH, broad s), 7.05 (2H, d), 6.82 (2H, d), 6.74(1H, s), 4.29 (2H, q), 3.78 (3H, s), 2.75 (2H, dd), 2.64 (2H, dd), 2.05(3H, s), 1.34 (3H, t) ppm. ¹³C (CDCl₃, 100 MHz): δ 158.8, 135.2, 131.7,130.4, 122.9, 120.8, 116.6, 114.7, 63.0, 61.0 56.3, 37.4, 29.2, 15.5,12.2 ppm.

Synthesis of4-[2-(4-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid(125)

4-[2-(4-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid(125) was synthesized from4-[2-(4-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (124) following the procedure described in Example 39.Purification: precipitation. Amount: 27.4 mg. ¹H (CD₃OD, 400 MHz): δ7.01 (2H, dd), 6.78 (2H, dd), 6.64 (1H, s), 3.30 (3H, s), 2.71 (2H, dd),2.62 (2H, dd), 1.98 (3H, s) ppm. ¹³C (CD₃OD, 100 MHz): δ 159.3, 135.5,132.7, 130.5, 122.7, 120.7, 117.5, 114.6, 55.6, 37.8, 29.3, 10.8 ppm.HPLC (20 min): 95.6%. LC/MS: 100%.

Example 45 Synthesis of4-[2-(3-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid(128)

Synthesis of4-[2-(3-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (126)

4-[2-(3-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (126) was synthesized from 5-methyl-1H-pyrrole-2-carboxylicacid ethyl ester (107) and (3-methoxyphenyl)-acetyl chloride followingthe procedure described in Example 32. Reaction Conditions:1,2-dichloroethane/−40° C. Purification: Recrystallization fromether/pentane. Yield: 50%. ¹H (CDCl₃, 400 MHz): δ 10.80 (NH, broad s),7.32 (1H, s), 7.18 (1H, dd), 6.85 (1H, d), 6.83 (1H, s), 6.75 (1H, d),4.33 (2H, q), 4.04 (2H, s), 3.74 (3H, s), 2.55 (3H, s), 1.36 (3H, t)ppm. 1³C (CDCl₃, 100 MHz): δ 194.3, 161.5, 159.7, 141.1, 136.7, 129.4,121.9, 121.6, 120.4, 117.2, 115.2, 112.1, 60.8, 55.1, 47.0, 14.4, 13.9ppm. LC/MS: 100%.

Synthesis of4-[2-(3-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (127)

4-[2-(3-Methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (127) was synthesized from4-[2-(3-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (126) following the procedure described in Example 32.Purification: Recrystallization from ether/pentane. Yield: 82%. ¹H(CDCl₃, 400 MHz): δ 9.40(NH,broad s), 6.74 (4H, m), 4.30 (2H, q), 3.77(3H, s), 2.78 (2H, dd), 2.67 (2H, dd), 2.08 (3H, s), 1.34 (3H, t) ppm.¹³C (CDCl₃, 100 MHz): δ 161.5, 159.6, 143.7, 131.0, 129.3, 121.8, 121.0,119.8, 115.7, 114.3, 111.2, 60.0, 55.2, 37.4, 27.9, 14.5, 11.1 ppm.LC/MS: 93%.

Synthesis of4-[2-(3-Methoxyphenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid(128)

To a solution of4-[2-(3-methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (127) in EtOH, 3 equiv of NaOH aq (3 M) was added then themixture was heated at 80° C. for 1 hour. When the reaction is judgedcomplete, the solvent was removed under vacuum, H₂O was added and anequal volume of Et₂O was added. The organic layer was removed then theaqueous layer was made acidic with HCl (1M). If the product precipitatedout at this point, it was filtered off, washed with H₂O, and dried toobtain pure desired product. If the product didn't crash out when theaqueous layer is made acidic, Et₂O was added, and the organic layer wasremoved (2×). The organic layer was dried with Na₂SO₄, filtered, andconcentrated to obtain desired product. Purification: Extraction.Amount: 37 mg. ¹H (CDCl₃, 400 MHz): δ 8.90 (NH, broad s), 7.19 (1H, dd),6.88 (1H, s), 6.75 (2H, m), 6.94 (1H, s), 3.78 (3H, s), 2.80 (2H, dd),2.68 (2H, dd), 2.08 (3H, s) ppm. ¹³C (CDCl₃, 100 MHz): δ 165.5, 159.6,143.5, 132.3, 129.3, 122.6, 121.0, 118.7, 117.8, 114.2, 111.2, 55.2,37.3, 27.8, 11.3 ppm. HPLC (20 min): 91.6%. LC/MS: 97%.

Example 46 Synthesis of5-Methyl-4-(2-naphthalen-1-yl-ethyl)-1H-pyrrole-2-carboxylic acid (131)

Synthesis of5-Methyl-4-(2-naphthalen-1-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (129)

5-Methyl-4-(2-naphthalen-1-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (129) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (107) and following the procedure described in Example 32.Reaction conditions: 1,2-dichloroethane/40° C. Purification: prep/HPLC.Yield: 52%. LC/MS: 62%.

Synthesis of5-Methyl-4-(2-naphthalen-]-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (130)

5-Methyl-4-(2-naphthalen-1-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (130) was synthesized from5-Methyl-4-(2-naphthalen-1-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (129) following the procedure described in Example 32.Purification: no purification.

Synthesis of5-Methyl-4-(2-naphthalen-]-yl-ethyl)-1H-pyrrole-2-carboxylic acid (131)

5-Methyl-4-(2-naphthalen-1-yl-ethyl)-1H-pyrrole-2-carboxylic acid (131)was synthesized from5-methyl-4-(2-naphthalen-1-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (130) following the procedure described in Example 45.Purification: prep HPLC. Amount: 5.2 mg. ¹H (CD₃OD, 400 MHz): δ 8.06(1H, d), 7.82(1H, d), 7.67 (1H, d), 7.45 (2H, m), 7.31 (1H, dd), 7.18(1H, d), 6.72 (1 H, s), 3.24 (2H, dd), 2.76 (2H, dd), 1.84 (3H, s) ppm.DEPT (CD₃OD, 100 MHz): CH₃: δ 10.8, CH₂: δ 28.4, 35.9, CH: 116.8, 124.8,126.4, 126.5, 126.7, 127.4, 127.6, 129.8 ppm. HPLC (20 min): 98.6%.LC/MS: 100%.

Example 47 Synthesis of5-Methyl-4-(3-naphthalen-2-yl-propyl)-1H-pyrrole-2-carboxylic acid (134)

Synthesis of5-Methyl-4-(3-naphthalen-2-yl-acryloyl)-1H-pyrrole-2-carboxylic acidethyl ester (132)

5-Methyl-4-(3-naphthalen-2-yl-acryloyl)-1H-pyrrole-2-carboxylic acidethyl ester (132) was synthesized from 5-methyl-1H-pyrrole-2-carboxylicacid ethyl ester (107) and-3-naphthalen-2-yl-acryloyl chloride followingthe procedure described in Example 32. Reaction conditions:1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS:40%.

Synthesis of5-Methyl-4-(3-naphthalen-2-yl-propyl)-1H-pyrrole-2-carboxylic acid ethylester (133)

5-Methyl-4-(3-naphthalen-2-yl-propyl)-1H-pyrrole-2-carboxylic acid ethylester (133) was synthesized from5-methyl-4-(3-naphthalen-2-yl-acryloyl)-1H-pyrrole-2-carboxylic acidethyl ester (132) following the procedure described in Example 32.Reduction of 132 gave both the reduction of the carbonyl and of thedouble bond. Purification: no purification. Yield: 100% by LC/MS.

Synthesis of5-Methyl-4-(3-naphthalen-2-yl-propyl)-1H-pyrrole-2-carboxylic acid (134)

5-Methyl-4-(3-naphthalen-2-yl-propyl)-1H-pyrrole-2-carboxylic acid (134)was synthesized from5-methyl-4-(3-naphthalen-2-yl-propyl)-1H-pyrrole-2-carboxylic acid ethylester (133) following the procedure described in Example 45.Purification: Extraction and prep HPLC. Amount: 20 mg. ¹H (CDCl₃, 400MHz): δ 8.95 (NH, broad s), 7.77 (3H, m), 7.60 (1H, s), 7.42 (2H, m),7.32 (1H, d), 6.89 (1H, s), 2.80 (2H, m), 2.46 (2H, m), 2.18 (3H, s),1.96 (2H, m) ppm. DEPT (CDCl₃, 100 MHz): CH₃: δ 11.6, CH₂: δ 25.2, 32.0,35.5, CH: 117.9, 125.0, 125.9, 126.4, 127.4, 127.6, 127.7, 127.8 ppm.HPLC (20 min): 88.4%. LC/MS: 94%.

Example 48 Synthesis of5-Methyl-4-(2-naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid (137)

Synthesis of5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (135)

5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (135) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acidethyl ester (107) and naphthalen-2-yl-acetyl chloride following theprocedure described in Example 32. Reaction Conditions:1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS:80%.

Synthesis of5-Methyl-4-(2-naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (136)

5-Methyl-4-(2-naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (136) was synthesized from5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (135) following the procedure described in Example 32.Purification: no purification.

Synthesis of5-Methyl-4-(2-naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid (137)

5-Methyl-4-(2-naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid (137)was synthesized from5-Methyl-4-(2-naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (136) following the procedure described in Example 45.Purification: prep HPLC. Amount: 12.6 mg. ¹H (CD₃OD, 400 MHz): δ 7.77(1H, d), 7.73 (2H, m), 7.54 (1H, s), 7.38 (2H, m), 7.28 (1H, dd), 6.68(1 H, s), 2.95 (2H, dd), 2.74 (2H, dd) ppm. ¹³C (CD₃OD, 100 MHz): δ165.8, 141.04, 135.15, 133.6, 131.9, 128.7, 128.6, 128.5, 128.4, 127.6,126.7, 126.1, 122.3, 122.0, 116.9, 38.8, 29.0, 10.9 ppm. HPLC (20 min):99.0%. LC/MS: 100%.

Example 49 Synthesis of5-Methyl-4-(2-phenyl-propyl)-1H-pyrrole-2-carboxylic acid (140)

Synthesis of 5-Methyl-4-(2-phenyl-propionyl)-1H-pyrrole-2-carboxylicacid ethyl ester (138)

5-Methyl-4-(2-phenyl-propionyl)-1H-pyrrole-2-carboxylic acid ethyl ester(138) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethylester (107) and 2-phenyl-propionyl chloride following the proceduredescribed in Example 32. Reaction conditions: 1,2-dichloromethane/−40°C.→RT. Purification: no purification. LC/MS: 86%.

Synthesis of 5-Methyl-4-(2-phenyl-propyl)-1H-pyrrole-2-carboxylic acidethyl ester (139)

5-Methyl-4-(2-phenyl-propyl)-1H-pyrrole-2-carboxylic acid ethyl ester(139) was synthesized from5-Methyl-4-(2-phenyl-propionyl)-1H-pyrrole-2-carboxylic acid ethyl ester(138) following the procedure described in Example 32. Purification: nopurification.

Synthesis of 5-Methyl-4-(2-phenyl-propyl)-1H-pyrrole-2-carboxylic acid(140)

5-Methyl-4-(2-phenyl-propyl)-1H-pyrrole-2-carboxylic acid (140) wassynthesized from 5-Methyl-4-(2-phenyl-propyl)-1H-pyrrole-2-carboxylicacid ethyl ester (139) following the procedure described in Example 45.Purification: prep HPLC. Amount: 13 mg. ¹H (CDCl₃, 400 MHz): δ 8.7(NH,.broad s), 7.27 (3H, m), 7.18 (2H, m), 6.77 (1H, s), 2.90 (1H, m),2.62 (2H, m), 1.97 (3H, s), 1.27 (3H, d) ppm. DEPT (CDCl₃, 100 MHz):CH₃: δ 11.3, 20.9 CH₂: δ 35.0, CH: 41.4, 118.6, 126.0, 127.1, 128.3 ppm.HPLC (20 min): 93.1%. LC/MS: 96%.

Example 50 Synthesis of4-(2-Naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid (128)

Synthesis of 4-(2-Naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (141)

4-(2-Naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethyl ester(141) was synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester andnaphthalen-2-yl-acetyl chloride following the procedure described inExample 32. Reaction Conditions: 1,2-dichloromethane/−40° C.→RT.Purification: no purification. LC/MS: 78%.

Synthesis of 4-(2-Naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acidethyl ester (142)

4-(2-Naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethyl ester(142) was synthesized from4-(2-Naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethyl ester(141) following the procedure described in Example 32. Purification: nopurification.

Synthesis of 4-(2-naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid(143)

4-(2-Naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid (143) wassynthesized from 4-(2-Naphthalen-2-yl-ethyl)-1H-pyrrole-2-carboxylicacid ethyl ester (142) following the procedure described in Example 45.Purification: silica gel chromatography (eluent: CH₂Cl₂→AcOEt). ¹H(MeOD, 400 MHz): δ 7.77 (3H, m), 7.61 (1H, s), 7.54 (1H, s), 7.38 (3H,m), 7.34 (1H, s), 6.68 (1 H, s), 3.01 (2H, dd), 2.86 (2H, dd) ppm. DEPT(MeOD, 100 MHz): CH₂: δ 29.8, 38.9, CH: 116.4, 122.7, 126.1, 126.8,127.5, 128.4, 128.5, 128.6, 128.7 ppm. HPLC (20 mn): 96.9% LC/MS: 100%

Example 51 Synthesis of4-(2-[4-Bromophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (146)

Synthesis of 4-(2-[4-bromophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylicacid ethyl ester (144)

4-(2-[4-Bromophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (144) was synthesized from 1H-pyrrole-2-carboxylic acid ethylester and 4-bromophenyl-2-yl-acetyl chloride following the proceduredescribed in Example 32. Reaction Conditions: 1,2-dichloromethane/−40°C.→RT. Purification: no purification.

Synthesis of 4-(2-[4-bromophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylicacid ethyl ester (145)

4-(2-[4-Bromophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (145) was synthesized from4-(2-[4-bromophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (144) following the procedure described in Example 32.Purification: no purification.

Synthesis of 4-(2-[4-bromophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid(146)

4-(2-[4-Bromophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (146) wassynthesized from4-(2-[4-bromophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (145) following the procedure described in Example 45.Purification: Crystallization from water. ¹H NMR (CD₃OD, 400 MHz): δ7.36 (2H, d), 7.07 (2H, d), 6.69 (1H, s); 6.67 (1H, s); 2.81 (2H, m);2.72 (2H, m) ppm. ¹³C NMR (CD₃OD, 100 MHz): 164.5, 142.7, 132.26, 131.6,125.9, 123.5, 122.8, 120.4, 116.4, 38.0, 29.7 ppm. HPLC (20 mn): 92.75%yield 91%.

Example 52 Synthesis of4-(2-[2-fluorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (149)

Synthesis of 4-(2-[4-fluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylicacid ethyl ester (147)

4-(2-[4-Fluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (147) was synthesized from 1H-pyrrole-2-carboxylic acid ethylester and (4-fluorophenyl)-2-yl-acetyl chloride following the proceduredescribed in Example 32. Reaction Conditions: 1,2-dichloromethane/−40°C.→RT. Purification: no purification.

Synthesis of 4-(2-[4-fluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylicacid ethyl ester (148)

4-(2-[4-Fluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (1481) was synthesized from4-(2-[4-fluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (147) following the procedure described in Example 32.Purification: no purification.

Synthesis of 4-(2-[4fluorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid(149)

4-(2-[4-Fluorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (149) wassynthesized from4-(2-[4-fluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (148) following the procedure described in Example 45.Purification: Crystallization from water. ¹H NMR (CDCl₃, 400 MHz): δ7.16 (2H, m), 7.03 (2H, m), 6.70 (2H, m); 2.87 (2H, m), 2.73 (2H, m)ppm. ¹³C NMR (CD₃OD, 100 MHz): 164.4, 161.4, 132.0, 130.0, 128.8, 126.0,125.0, 123.5, 122.8, 116.4, 115.8, 31.8, 28.5 ppm. Yield 71%. HPLC 20min: 97.76%.

Example 53 Synthesis of4-(2-[4-methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (152)

Synthesis of 4-(2-[4-methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylicacid ethyl ester (150)

4-(2-[4-Methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (150) was synthesized from 1H-pyrrole-2-carboxylic acid ethylester and p-tolyl-2-yl-acetyl chloride following the procedure describedin Example 32. Reaction Conditions: 1,2-dichloromethane/40° C.→RT.Purification: no purification.

Synthesis of 4-(2-[4-methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylicacid ethyl ester (151)

4-(2-[4-Methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (151) was synthesized from4-(2-[4-methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (150) following the procedure described in Example 32.Purification: no purification.

Synthesis of 4-(2-[4-methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid(152)

4-(2-[4-Methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (152) wassynthesized from4-(2-[4-methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (151) following the procedure described in Example 45.Purification: Crystallization from water. ¹H NMR (CDCl₃, 400 MHz): δ7.04 (4H, m), 6.68 (1H, s); 6.67 (1H, s); 2.78 (2H, m), 2.72 (2H, m),2.27 (3H, s) ppm. ¹³C (CD₃OD, 100 MHz): 164.5, 140.3, 136.2, 129.9,129.4, 126.5, 123.3, 122.7, 116.5, 38.3, 30.1, 21.1 ppm. Yield 55%. HPLC20 mn: 96.23%

Example 54 Synthesis of4-(2-[2-methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (155)

Synthesis of 4-(2-[2-methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylicacid ethyl ester (153)

4-(2-[2-Methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (153) was synthesized from 1H-pyrrole-2-carboxylic acid ethylester and o-tolyl-2-yl-acetyl chloride following the procedure describedin Example 32. Reaction Conditions: 1,2-dichloromethane/−40° C.→RT.Purification: no purification.

Synthesis of 4-(2-[2-methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylicacid ethyl ester (154)

4-(2-[2-Methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (154) was synthesized from4-(2-[2-methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (153) following the procedure described in Example 32.Purification: no purification.

Synthesis of 4-(2-[2-methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid(155)

4-(2-[2-Methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (155) wassynthesized from4-(2-[2-methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (153) following the procedure described in Example 45.Purification: Crystallization from water. ¹H NMR (CDCl₃, 400 MHz): δ7.08 (4H, m), 6.71 (1H, s); 6.69 (1H, s); 2.83 (2H, m), 2.69 (2H, m),2.27 (3H, s) ppm. ¹³C (CD₃OD, 100 MHz): 164.5, 141.5, 136.9, 131.0,130.0, 127.0, 126.9, 126.58, 123.4, 122.6, 116.4, 63.1, 28.9, 19.4 ppm.Yield 73% HPLC 20 mn: 96.95%

Example 55 Synthesis of4-(2-[3-methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (158)

Synthesis of 4-2-[3-methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylicacid ethyl ester (156)

4-(2-[3-Methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (156) was synthesized from 1H-pyrrole-2-carboxylic acid ethylester and m-tolyl-2-yl-acetyl chloride following the procedure describedin Example 32. Reaction Conditions: 1,2-dichloromethane/−40° C.→RT.Purification: no purification.

Synthesis of 4-(2-[3-methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylicacid ethyl ester (157)

4-(2-[3-Methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (157) was synthesized from4-(2-[3-methylphenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethylester (156) following the procedure described in Example 32.Purification: no purification.

Synthesis of 4-(2-[3-methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid(158)

4-(2-[3-Methylphenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (158) wassynthesized from4-2-[3-methylphenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (157) following the procedure described in Example 45.Purification: Crystallization from water. ¹H NMR (CDCl₃, 400 MHz): δ9.00 (1H, broad s), 7.18 (1H, m), 7.00.(3H, m), 6.91 (1H, s), 6.75 (1H,s), 2.82 (4H, m), 2.38 (3H, s) ppm. LC/MS: 100%, m/z=229 g/mol.Yield=72%.

Example 56 Synthesis of4-(2-[2-chloro-4-fluorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (161)

Synthesis of4-(2-[2-chloro-4-fluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester

4-(2-[2-chloro4-fluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (159) synthesized from 1H-pyrrole-2-carboxylic acid ethylester and (2-chloro4-fluorophenyl)-2-yl-acetyl chloride following theprocedure described in Example 32. Reaction Conditions:1,2-dichloromethane/−40° C.→RT. Purification: no purification.

Synthesis of4-(2-[2-chloro-4-fluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acidethyl ester (160)

4-(2-[2-chloro4-fluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acidethyl ester (160) was synthesized from4-(2-[2-chloro4-fluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (159) following the procedure described in Example 32.Purification: no purification.

Synthesis of4-(2-[2-chloro-4-fluorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (161)

4-(2-[2-chloro4-fluorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (161)was synthesized from4-(2-[2-chloro4-fluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acidethyl ester (160) following the procedure described in Example 45.Purification: precipitation from water. ¹H NMR (CDCl₃, 400 MHz): δ 7.19(2H, m), 6.96 (1H, m); 6.70 (2H, m); 2.95 (2H, m), 2.73 (2H, m) ppm. ¹³CNMR (CD₃OD, 100 MHz): 164.4, 161.2, 136.9, 135.4, 132.9, 125.7, 123.6,122.7, 117.4, 116.4, 114.7, 35.7, 28.0 ppm. Yield 51%. HPLC 20 mn:98.85%

Example 57 Synthesis of4-(2-[2,4-dichlorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (164)

Synthesis of4-(2-[2,4-dichlorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (162)

4-(2-[2,4-dichlorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (162) was synthesized from 1H-pyrrole-2-carboxylic acidethyl ester and o,p-dichlorophenyl-2-yl-acetyl chloride following theprocedure described in Example 32. Reaction Conditions:1,2-dichloromethane/−40° C.→RT. Purification: no purification.

Synthesis of4-(2-[2,4-dichlorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (163)

4-(2-[2,4-dichlorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (163) was synthesized from4-(2-[2,4-dichlorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (162) following the procedure described in Example 32.Purification: no purification.

Synthesis of 4-(2-[2,4-dichlorophenyl]-ethyl)-1H-pyrrole-2-carboxylicacid (164)

4-(2-[2,4-dichlorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (164) wassynthesized from4-(2-[2,4-dichlorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (163) following the procedure described in Example 45 (Note:reaction solvent changed to ethanol). Purification: precipitation fromwater. ¹H NMR (CD₃OD, 400 MHz): δ 7.43 (1H, s), 7.20 (2H, m), 6.69 (2H,s), 2.96 (2H, t), 2.78 (2H, t) ppm. Yield=46%.

Example 58 Synthesis of4-(2-[3,4-dichlorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (167)

Synthesis of4-(2-[3,4-dichlorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (165)

4-(2-[3,4-dichlorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (165) was synthesized from 1H-pyrrole-2-carboxylic acidethyl ester and m,p-dichlorophenyl-2-yl-acetyl chloride following theprocedure described in Example 32. Reaction Conditions:1,2-dichloromethane/−40° C.→RT. Purification: no purification.

Synthesis of4-(2-[3,4-dichlorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (166)

4-(2-[3,4-dichlorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (166) was synthesized from4-(2-[3,4-dichlorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (165) following the procedure described in Example 32.Purification: no purification.

Synthesis of 4-(2-[3,4-dichlorophenyl]-ethyl)-1H-pyrrole-2-carboxylicacid (167)

4-(2-[3,4-dichlorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (167) wassynthesized from4-(2-[3,4-dichlorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (166) following the procedure described in Example 45 (Note:reaction solvent changed to ethanol). Purification: precipitation fromwater. ¹H NMR (CD₃OD, 400 MHz): δ 7.36 (22H, m), 7.08 (1H, m), 6.68 (2H,m), 2.83 (4H, m) ppm. Yield=87%.

Example 59 Synthesis of4-(2-[2,4-difluorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (170)

Synthesis of4-(2-[2,4-difluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (168)

4-(2-[2,4-Difluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (168) was synthesized from 1H-pyrrole-2-carboxylic acidethyl ester and o,p-difluorophenyl-2-yl-acetyl chloride following theprocedure described in Example 32. Reaction Conditions:1,2-dichloromethane/−40° C.→RT. Purification: no purification.

Synthesis of4-(2-[2,4-difluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (169)

4-(2-[2,4-difluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (169) was synthesized from4-(2-[2,4-difluorophenyl]-2-yl-acetyl)-1H-pyrrole-2-carboxylic acidethyl ester (168) following the procedure described in Example 32.Purification: no purification.

Synthesis of 4-(2-[2,4-difluorophenyl]-ethyl)-1H-pyrrole-2-carboxylicacid (170)

4-(2-[2,4-difluorophenyl]-ethyl)-1H-pyrrole-2-carboxylic acid (170) wassynthesized from4-(2-[2,4-difluorophenyl]-2-yl-ethyl)-1H-pyrrole-2-carboxylic acid ethylester (169) following the procedure described in Example 45.Purification: precipitation from water. ¹H NMR (CDCL₃, 400 MHz): δ 6.76(2H, m), 6.70 (3H, m); 2.87 (2H, m), 2.75 (2H, m) ppm. ¹³C NMR (CD₃OD,100 MHz): 165.6, 164.5, 163.2, 148.0, 125.6, 123.6, 122.7, 116.3, 112.4,112.2, 101.9, 38.3, 29.2 ppm. Yield 70%. HPLC 20 mn: 99.05%

Example 60 Synthesis of 4,5,6,7-tetrahydro-2H-isoindole-1-carboxylicacid (172)

Synthesis of 4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid ethylester (171)

1,8-Diazabicyclo[5.4.0]-undec-7-ene (6.2 mL, 41.5 mmol) in 2-propanol(45 mL) was added addition funnel over 25 minutes to a stirring solutionof 1-nitrocyclohexene (5.0441 g, 39.67 mmol) and ethylisocyanoacetate(4.3340 g, 37.16 mmol) in THF (45 mL). The reaction was judged completeafter stirring overnight at room temperature. 2N HCl (˜100 mL) and EtOAc(˜50 mL) were added. The organic layer was removed, then washed withH₂O, 5% NaHCO₃, and H₂O. The crude product was dried with Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography(Combiflash column, 100% CH₂Cl₂) to obtain 171 contaminated with a minorimpurity. Attempts to recrystallize from hexanes were unsuccessful atremoving the impurity, so the product was carried on to the next stepwith no further purification. ¹H (CDCl₃, 400 MHz): δ 9.01 (1H, broad s),6.64 (1H, s), 4.31 (3H, q, J=7.2 Hz), 2.82 (2H, t, J=5.6 Hz), 2.55 (2H,t, J=5.6 Hz), 1.80-1.68 (4H, m), 1.36 (3H, t, J=7.2 Hz) ppm. ¹³C (CD₃OD,100 MHz): δ 161.71, 128.06 and 127.84, 121.98 and 121.96, 118.74 and118.55, 118.03 and 117.71, 59.62, 23.41 and 23.39, 23.36 and 23.33,23.16 and 23.13, 21.88 and 21.86, 14.48ppm. DEPT (CD₃OD, 100 MHz): CH₃carbons: 14.48; CH₂ carbons: 59.62, 23.41 and 23.39, 23.36 and 23.33,23.16 and 23.13, 21.88 and 21.86; CH carbons: 118.74 and 118.55 ppm.HPLC: 10.689 min.

Synthesis of 4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (172)

Freshly prepared aq. NaOH (10 M in H₂O, 10.3 mmol) was added to astirring, room temperature solution of 171 (0.3966 g, 2.05 mmol) in MeOH(5.1 mL, 0.4 M) under N₂. The reaction was then heated to reflux for 20minutes. A small amount of starting material remained. A large amount ofundesired product along with only a small amount of desired product wasobserved by HPLC. The reaction was concentrated, redissolved in H₂O, andextracted with EtOAc (1 mL). 10% aq. HCl was added dropwise to theaqueous layer until the pH=2. The white solid that precipitated from thereaction was filtered off and washed with cold H₂O. The solid was driedunder vacuum overnight to obtain 0.0076 g (11.6%) of 172. ¹H (CD₃OD, 400MHz): δ 5.62 (1H, s), 2.77 (2H, t, J=5.6 Hz), 2.52 (2H, t, J=5.4 Hz),1.78-1.66 (4H, m) ppm. ¹³C (CD₃OD, 100MHz): δ 164.87, 129.69, 122.48,120.57, 118.42, 24.74, 24.69, 24.35, 22.94 ppm. DEPT (CD₃OD, 100 MHz):CH₂ carbons: 24.74, 24.69, 24.35, 22.94; CH carbons: 120.57 ppm. HPLC:8.896 min.

Example 61 Synthesis of5-bromo-4-[2-(2-bromophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (173)

Synthesis of 5-bromo-4-[2-(2-bromophenyl)-ethyl]-1H-pyrrole-2-carboxylicacid (173)

Bromine (0.021 mL, 0.414 mmol) was added dropwise over 5 minutes to astirring solution of 65 (0.1014 g, 0.345 mmol) in acetic acid (1.1 mL).When the reaction was judged complete by HPLC (20 min), H₂O was added,and the solid that precipitated was filtered off and washed with H₂O.The light purple solid that was obtained was dissolved in EtOAc, washedwith Na₂SO₃ and H₂O, then dried with Na₂SO₄, filtered, and concentrated.The product was purified by preparative reverse phase HPLC with 40:60H₂O:CH₃CN (w/0.05% TFA); 20 mL/min.; λ=214 nM. 0.0574 g (44.6%) of 173was obtained as a fluffy pale pink solid. ¹H (CD₃OD, 400 MHz): δ 7.50(1H, d, J=7.8 Hz), 7.24-7.00 (3H, m), 6.68 (1H, s), 2.92 (2H, t, J=˜7.8Hz), 2.67 (2H, t, J=˜7.8 Hz) ppm. Partial ¹³C (CD₃OD, 100 MHz): δ163.25, 141.86, 133.73, 131.85, 128.89, 128.54, 125.26, 124.68, 117.16,105.89, 37.91, 27.62 ppm. DEPT (CD₃OD, 100 MHz): CH₂ carbons: 37.91,27.62; CH carbons: 133.73, 131.85, 128.89, 128.54, 117.16 ppm. HPLC:10.473 min.

Example 62 Synthesis of5-bromo-4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (174)

Synthesis of5-bromo-4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (174)

5-Bromo-4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid wasmade using the procedure in Example 61. ¹H (CD₃OD, 400 MHz): δ 7.22 (2H,d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.65 (1H, s), 2.81 (2H, t, J=7.3Hz), 2.67 (2H, t, J=7.3 Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ 163.33, 141.42,132.54, 131.03, 129.18, 124.73, 117.46, 105.84, 36.72, 29.04 ppm.

Example 63 Synthesis of 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid(177)

Synthesis of 5-(3-phenylpropionyl)1H-pyrrole-2-carboxylic acid ethylester (175) and 4-(3-phenylpropionyl)-1H-pyrrole-2-carboxylic acid ethylester (43)

Ethylpyrrole-2-carboxylate (2.0211 g, 14.5 mmol) in a minimal amount ofdichloroethane (2 mL) was added to an ice cooled stirring mixture ofzinc chloride (4.0151 g, 29.5 mmol) and hydrocinnamoyl chloride (5.0348g, 29.9 mmol) in dichloroethane (20 mL, 0.66 M) under N₂. After stirring10 min, the ice bath was removed, and the reaction was allowed to warmto room temperature until it was judged complete by HPLC (2 h 45 min).PS-Trisamine™ resin (13.44 g) was added, and the reaction was stirred atroom temperature for about 1.5 h. The reaction was filtered through afrit into a flask containing ice water. The frit was washed with CH₂Cl₂,then the combined organics were washed with H₂O, dried with Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography(Combiflash column, 25:75 Hexanes:CH₂Cl₂) to obtain 0.5374 g (14%) of175 (lower Rf). No attempt was made to isolate 43 (higher Rf). HPLC:10.58 min. (Starting material: 8.90 min.)

Synthesis of 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester(176)

Triethylsilane (0.977 mL, 6.14 mmol) was added to a stirring, roomtemperature solution of 5-(3-phenylpropionyl)1H-pyrrole-2-carboxylicacid ethyl ester (175) (0.5374 g, 1.98 mmol) in trifluoroacetic acid(TFA) (4.72 mL, 0.42 M) under N₂. The reaction was judged complete byHPLC after stirring at room temperature overnight. The TFA was removedunder vacuum, and the crude product was purified by preparative reversephase HPLC with the following conditions: 35:65 H₂O:CH₃CN; 20 mL/min.;λ=254 nM. HPLC: 11.12 min.

Synthesis of 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid (177)

Freshly prepared aq. NaOH (10 M in H₂O, 1.22 mmol) was added to astirring, room temperature solution of5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (85) (0.0629g, 0.244 mmol) in MeOH (0.61 mL, 0.4 M) under N₂. The reaction washeated to reflux until the reaction was judged complete by HPLC. Theproduct was concentrated and then 2 mL of diethyl ether and 2 mL of H₂Owere added. The organic layer was removed and discarded, then 2 mL ofdiethyl ether was added, and 10% aq. HCl was added dropwise until thepH=2. The diethyl ether later was removed, and the aqueous was extractedwith another portion of diethyl ether. The combined organics were dried,and concentrated to provide the desired product. (Note: An undesiredimpurity has a retention time of 10.85 min by HPLC. HPLC: 9.91 min.

Example 64 Conversion of4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid to the sodiumsalt (178)

Formation of the sodium salt of4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (178)

4-[2-(4-Chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid (39) (4.2668g, 17.09 mmol) was dissolved in 60 mL (0.17 M) of MeOH. The solution wascooled in a 0° C. ice bath, then an aqueous solution of sodium hydroxide(0.6872 g, 17.09 mmol NaOH, 2.7 M) slowly with stirring. A white solidoiled out of solution. The methanol was removed on the rotovap, then 32mL of H₂O was added, and flask was mixed well to dissolve at roomtemperature. The slight pink discoloration observed when the startingacid was dissolved in methanol was removed when the solution wasfiltered through filter paper. Lyophilization of the colorless solutionprovided 4.5345 g (97.7%) of a fluffy white solid.

Example 65 Synthesis of 4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylicacid ethyl ester (182)

Synthesis of 4-Nitro-1-phenyl-pentan-3-ol (179)

Following the procedure of One et al, J. Heterocyclic Chem., 1994, 31,707-710, which is incorporated by reference, nitroethane (10 mL, 139.2mmol, 96%) and 3-phenylpropionaldehyde (18.49 mL, 139.9 mmol) weredissolved in THF (70 mL, 2 M). After cooling to −10° C. in a brine bath,1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (1.46 mL, 9.74 mmol) wasadded, and allowed to stir until complete by HPLC (75 min). The reactionwas diluted with diethyl ether and H₂O, and then the organic was removedand washed with saturated aqueous NaHCO₃ and brine. The aqueous layerswere back-extracted with diethyl ether, and the combined organics weredried with Na₂SO₄, filtered, and concentrated to provide 179, which wasused without further purification in the next step. HPLC: 9.68 min.(Note: The retention time for the starting materials follow:nitroethane: 6.49 min.; 3-phenylpropionaldehyde: 9.45 min).

Synthesis of Acetic acid 2-nitro-1-phenethylpropyl ester (180)

Crude 4-Nitro-1-phenyl-pentan-3-ol (179) from above was dissolved inCH₂Cl₂ (60 mL) and cooled in an ice bath under nitrogen. Concentratedsulfuric acid (0.76 mL, 14.2 mmol) then acetic anhydride (13.83 mL,146.2 mmol) were added slowly, and the reaction was allowed to warm toroom temperature, and was stirred until judged complete by HPLC (3 h, 40min). (Note: The reaction turned black soon after the addition of theacetic anhydride.) The reaction was quenched by pouring slowly intowater, then the organic layer was removed, washed with aq. NaHCO₃,dried, filtered, and concentrated. The crude product was purified bypurified by silica gel chromatography (Combiflash column, 95:5Hexanes:EtOAc) to achieve pure 180 (21.4447 g, 65.5%, 2 steps). HPLC:10.45 min.

Synthesis of 4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid ethylester (181)

Acetic acid 2-nitro-1-phenethylpropyl ester (180) (10.4302 g, 44.2 mmol)and ethyl isocyanoacetate (4.957 g, 44.2 mmol) were weighed out into a250 mL round bottom flask. The flask was sealed with a septum, purgedwith nitrogen, then dissolved in a solution of THF and iso-propylalcohol (1.6:1, 44 mL, 1M). The reaction was cooled in an ice bath, thenDBU (13.6 mL, 2.05 mmol) was added. The reaction was allowed to warm toroom temperature, and was allowed to stir at room temperature untiljudged complete by HPLC (2 h, 25 min.). The reaction was diluted withH₂O and diethyl ether, and the organic layer was removed, extracted with2N HCl, H₂O, and NaHCO₃. The combined organics were dried with Na₂SO₄,filtered, and concentrated. The crude product was purified by purifiedby silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc).The product crystallized from the combined Combiflash fractions toobtain a batch of 3.3224 g (29%) of pure 181 and 3.7709 g of 181containing a small amount of impure material. HPLC: 11.27 min.

Synthesis of 4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid (182)

4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (181) washydrolyzed as described above to obtain pure desired product. 1H (CD₃OD,400 MHz): δ 10.60 (1H, br s), 7.24-7.00 (5H, m), 6.62 (1H, s), 2.99 (2H,dd, J=9.6, 7.3 Hz), 2.67 (2H, dd, J=9.6, 7.8 Hz), 1.83 (3H, s) ppm. ¹³C(CD₃OD, 100 MHz): δ 164.75, 143.86, 132.12, 129.58, 129.10, 126.61,122.27, 122.10, 120.68, 38.32, 28.61, 9.80 ppm. DEPT (CD₃OD, 100 MHz):CH₂ carbons: 38.32, 28.61; CH carbons: 129.58, 129.10, 126.61, 122.27ppm. HPLC: 9.947 min.

Example 66 Synthesis of4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester(38)

Synthesis of 4-[2-(4-chlorophenyl)-ethyl]-1H-pyrrole-2-carboxylic acidamide (38)

To a solution of 39 (0.5026 g, 2.01 mmol) in CH₂Cl₂ (8.4 mL, 0.24 M) wasadded 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimidehydrochloride(EDCI, 0.4700 g, 2.42 mmol), 4-(dimethylamino)pyridine (DMAP, 0.0270 g,0.20 mmol), and EtOH (0.352 mL, 6.04 mmol), and the reaction was stirredat room temperature overnight. The solid by-product was filtered off andrinsed with CH₂Cl₂, then the combined organics were washed with 5% aq.NaHCO₃, 5% aq. HCl, and H₂O. The combined organics were dried withNa₅SO₄, filtered, and concentrated. The product was purified by silicagel chromatography (Combiflash column, 90:10 Hexanes:EtOAc) to obtain0.2974 g (53.2%) of 38. The analytical data for 38 matched that whensynthesized before by a different method. HPLC: 11.261 min. (Note: HPLCof starting material=10.028 min.)

Example 67 Synthesis of 4-Phenylaminomethyl-1H-pyrrole-2-carboxylic acid(184)

Synthesis of 4-Phenylaminomethyl-1H-pyrrole-2-carboxylic acid ethylester (183)

0.2012 g (1.20 mmol) of 4-formyl-1H-pyrrole-2-carboxylic acid ethylester was dissolved in 4.8 mL (0.25 M) of 5% acetic acid in methanol.Aniline (0.13 mL g, 1.44 mmol) was added, and the reaction was stirredat room temperature under nitrogen for 45 minutes, then sodiumcyanoborohydride (0.1244 g, 1.98 mmol) was added slowly and the reactionwas allowed to stir at room temperature overnight. About 2 m]L ofsaturated K₂CO₃ were added, and the reaction was extracted twice withethyl acetate. The combined organics were washed with saturated NaHCO₃(˜3 mL) and brine (˜3 mL), then the combined organics were dried withNa₂SO₄, filtered and concentrated en vacuo. The crude product waspurified by silica gel chromatography (Combiflash column, 85:15Hexanes:Ethyl acetate) to obtain 0.2663 g (91%) of4-phenylaminoethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (183) as acolorless viscous oil. Note: Starting material4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has an HPLC retentiontime=7.337 min. ¹H (CDCl₃, 400 MHz): δ 9.49 (1H, broad s), 7.19 (2H, dd,J=8.6, 7.3 Hz), 6.73 (1H, tt, J=7.3, 1.1 Hz), 6.66 (2H, dd, J=8.6, 1.1Hz), 6.91 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=2.0 Hz), 4.33 (2H, q, J=7.2Hz), 4.19 (2H, s), 3.90 (1H, broad s), 1.36 (3H, t, J=7.2 Hz) ppm. HPLC:6.936 min.

Synthesis of 4-Phenylaminomethyl-1H-pyrrole-2-carboxylic acid (184)

4-phenylaminomethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (183)(0.0773 g, 0.316 mmol) was weighed out into a round bottom flask. A stirbar, condenser, and septum are added, and the flask was purged with N₂.The ester was dissolved in EtOH (0.70 mL, 0.45 M), and then freshlyprepared aqueous NaOH (0.0354 g, 0.283 mL H₂O) was added with stirringto the ester solution. The reaction flask was immediately immersed in anoil bath preheated to 85° C., and the reaction was heated and stirredunder N₂ until judged complete by HPLC (15 min). The solvent was removedon the rotovap, and 0.8 mL H₂O was added. The aqueous layer was slowlyand carefully made acidic with 10% aqueous HCl. The product was purifiedby reverse phase preparative HPLC (45:55 H₂O with 0.05% TFA: CH₃CN with0.05% TFA) to obtain pure 4-phenylaminomethyl-1H-pyrrole-2-carboxylicacid. ¹H (CD₃OD, 400 MHz): δ 7.51-7.40 (5H, m), 6.99 (1H, d, J=1.5 Hz),6.86 (1H, d, J=1.5 Hz), 4.46 (2H, s) ppm. ¹³C(CD₃OD, 100MHz): δ 163.92,137.17, 131.10, 129.97, 125.95, 125.07, 123.71, 117.37, 115.77, 49.38ppm. DEPT (CD₃OD, 100 MHz): CH₂ carbons: 49.38; CH carbons: 131.10,129.97, 125.94, 123.71, 117.37 ppm. HPLC: 5.724 min.

Example 68 Synthesis of4-[(Acetylphenylamino)-methyl]-1H-pyrrole-2-carboxylic acid (186)

Synthesis of 4-[(Acetylphenylamino)-methyl]-1H-pyrrole-2-carboxylic acidethyl ester (185)

4-Phenylaminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183)(0.1523 g, 0.623 mmol) was weighed out into a 10 mL flask. A stir barand septum were added, and the flask was purged with nitrogen. The aminewas dissolved in methylene chloride (1.6 mL, 0.4 M) and then the flaskwas cooled to 0° C. N,N-diisopropyl ethyl amine (0.1194 mL, 0.686 mmol)was added, then acetyl chloride (0.0488 mL, 0.686 mmol) was added slowlyby syringe to the stirring 0° C. solution. The reaction was then allowedto warm to room temperature. When the reaction was judged complete byHPLC (35 min) the reaction was diluted with methylene chloride andquenched with water. The organic phase was removed, washed with brine,dried with Na₂SO₄, filtered and concentrated en vacuo. The crude productwas sufficiently pure by HPLC and NMR analysis that it was used in thenext step without further purification (0.1625 g, 91%, white crystallinesolid). ¹H (CD₃OD, 400 MHz): δ 11.22 (1H, broad s), 7.43-7.31 (3H, m),7.08 (2H, dd, J=7.0, 1.5 Hz), 6.75 (1H, d, J=1.5 Hz), 6.68 (1H, d, J=1.5Hz), 4.70 (2H, s), 4.24 (2H, q, J=7.0 Hz), 1.81 (3H, s), 1.31 (3H, t,J=7.0 Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ 172.47, 162.64, 143.86, 130.68,129.34, 129.27, 124.50, 124.33, 122.19, 116.72, 61.16, 46.60, 22.64,14.75 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons: 22.64, 14.75; CH₂carbons: 61.16, 46.60; CH carbons: 130.68, 129.34, 129.27, 124.33,116.72 ppm. HPLC: 8.738 min.

Synthesis of 4-(Acetylphenylamino)-methyl]-1H-pyrrole-2-carboxylic acid(186)

4-[(Acetylphenylamino)-methyl]-1H-pyrrole-2-carboxylic acid ethyl ester(185) (0.1353 g, 0.473 mmol) was weighed out into a round bottom flask.A stir bar, condenser, and septum are added, and the flask was purgedwith N₂. The ester was dissolved in EtOH (1.05 mL, 0.45 M), and thenfreshly prepared aqueous NaOH (0.0529 g, 0.42 mL H₂O) was added withstirring to the ester solution. The reaction flask was immediatelyimmersed in an oil bath preheated to 85° C., and the reaction was heatedand stirred under N₂ until judged complete by HPLC (45 min). The solventwas removed on the rotovap, and 1.0 mL CH₂Cl₂ and 1.0 mL H₂O were added.The aqueous layer was slowly and carefully made acidic with 10% aqueousHCl. Although the aqueous got cloudy, no precipitate crashed out. Theproduct was extracted from the aqueous layer with three portions ofCH₂Cl₂, dried with Na₂SO₄, filtered, and concentrated en vacuo to obtainpure 4-[(Acetylphenylamino)-methyl]-1H-pyrrole-2-carboxylic acid (186,0.0968 mg, 79%). ¹H (CD₃OD, 400 MHz): δ 11.11 (1H, broad s), 7.46-7.31(3H, m), 7.09 (2H, dd, J=7.0, 1.5 Hz), 6.74 (1H, s), 6.68 (1H, s),4.71(2H, s), 1.82 (3H, s) ppm. ¹³C (CD₃OD, 100 MHz): δ 172.49, 164.19,143.87, 130.69, 129.37, 129.28, 124.41, 124.24, 122.14, 116.88, 46.64,22.64 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons: 22.64; CH₂ carbons:46.64; CH carbons: 130.69, 129.37, 129.28, 124.24, 116.88 ppm. HPLC:7.518min.

Example 69 Synthesis of4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid (188)

Synthesis of 4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylicacid ethyl ester (187)

0.5052 g (3.02 mmol) of 4-formyl-1H-pyrrole-2-carboxylic acid ethylester was dissolved in 12.0 mL (0.25 M) of 5% acetic acid in methanol.4-chloroaniline (0.4633 g, 3.63 mmol) was added, and the reaction wasstirred at room temperature under nitrogen for 30 minutes, then sodiumcyanoborohydride (0.3013 g, 4.79 mmol) was added slowly and the reactionwas allowed to stir at room temperature overnight. About 5 mL ofsaturated K₂CO₃ were added, and the reaction was extracted twice withethyl acetate. The combined organics were washed with saturated NaHCO₃(˜6 mL) and brine (˜6 mL), then the combined organics were dried withNa₂SO₄, filtered and concentrated en vacuo. The crude product waspurified by silica gel chromatography (Combiflash column, 85:15Hexanes:Ethyl acetate) to obtain 0.5806 g (69%) of4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid ethylester (187) as a light tan solid. Note: Starting material4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has an HPLC retentiontime=7.337 min. HPLC: 8.543 min.

Synthesis of 4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylicacid (188)

4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid ethylester (187) (0.1070 g, 0.384 mmol) was weighed out into a round bottomflask. A stir bar, condenser, and septum are added, and the flask waspurged with N₂. The ester was dissolved in EtOH (0.85 mL, 0.45 M), andthen freshly prepared aqueous NaOH (0.0432 g, 0.123 mL H₂O) was addedwith stirring to the ester solution. The reaction flask was immediatelyimmersed in an oil bath preheated to 85° C., and the reaction was heatedand stirred under N₂ until judged complete by HPLC (30 min). The solventwas removed on the rotovap, and 0.8 mL H₂O was added. The aqueous layerwas slowly and carefully made acidic with 10% aqueous HCl. The productwas purified by reverse phase preparative HPLC (45:55 H₂O with 0.05%TFA:CH₃CN with 0.05% TFA) to obtain pure4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid (188). ¹H(CD₃OD, 400 MHz): 7.12 (2H, d, J=8.4 Hz), 6.92 (1H, s), 6.85 (1H, s),6.95 (2H, d, J=8.4 Hz), 4.16 (2H, s) ppm. ¹³C (CD₃OD, 100 MHz): δ164.24, 146.44, 129.96, 124.87, 124.15, 123.56, 122.98, 117.22, 116.24,43.18 ppm. DEPT (CD₃OD, 100 MHz): CH₂ carbons: 43.18; CH carbons:129.96, 123.56, 117.22, 116.24 ppm. HPLC: 7.137 min.

Example 70 Synthesis of4-[(Acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acid(190)

Synthesis of4-[(Acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acidethyl ester (189)

4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid ethylester (187) (0.2868 g, 1.03 mmol) was weighed out into a 10 mL flask. Astir bar and septum were added, and the flask was purged with nitrogen.The amine was dissolved in methylene chloride (2.6 mL, 0.4 M) and thenthe flask was cooled to 0° C. N,N-diisopropyl ethyl amine (0.1971 mL,1.13 mmol) was added, then acetyl chloride (0.0805 mL, 1.13 mmol) wasadded slowly by syringe to the stirring 0° C. solution. The reaction wasthen allowed to warm to room temperature. When the reaction was judgedcomplete by HPLC (90 min) the reaction was diluted with methylenechloride and quenched with water. The organic phase was removed, washedwith brine, dried with Na₂SO₄, filtered and concentrated en vacuo. Thecrude product was purified by silica gel chromatography (Combiflashcolumn, 2:1 Hexanes:Ethyl acetate) to obtain pure4-[(acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acidethyl ester (189, 0.2701 g, 82%) as a sticky white solid. ¹H (CD₃OD, 400MHz): δ 11.25 (1H, broad s), 7.35 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4Hz), 6.76 (1H, s), 6.69 (1H, s), 4.68 (2H, s), 4.22 (2H, q, J=7.1 Hz),1.81 (3H, s), 1.29 (3H, t, J=7.1 Hz) ppm. ¹³C (CD₃OD, 100 MHz): δ172.17, 162.50, 142.39, 134.87, 130.94, 130.70, 124.46 & 124.30, 123.94,121.91 & 121.88, 116.64, 61.13, 46.43, 22.70, 14.75 ppm. DEPT (CD₃OD,100 MHz): CH₃ carbons: 22.70, 14.75; CH₂ carbons: 61.13, 46.43; CHcarbons: 130.94, 130.70, 124.46 & 124.30, 116.64 ppm. HPLC: 9.247 min.

Synthesis of4-[(Acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acid(190)

4-[(acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acidethyl ester (0.2701 g, 0.842 mmol) was weighed out into a round bottomflask. A stir bar, condenser, and septum are added, and the flask waspurged with N₂. The ester was dissolved in EtOH (1.87 mL, 0.45 M), andthen freshly prepared aqueous NaOH (0.0943 g, 0.75 mL H₂O) was addedwith stirring to the ester solution. The reaction flask was immediatelyimmersed in an oil bath preheated to 85° C., and the reaction was heatedand stirred under N₂ until judged complete by HPLC (11 min). The solventwas removed on the rotovap, and 1.6 mL CH₂Cl₂ and 1.6 mL H₂O were added.The aqueous layer was slowly and carefully made acidic with 10% aqueousHCl. The product oiled out. The product was extracted from the aqueouslayer with three portions of CH₂Cl₂, dried with Na₂SO₄, filtered, andconcentrated en vacuo to obtain pure4-[(Acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acid(190, 0.2242 mg, 91%). ¹H (CD₃OD, 400 MHz): δ 11.14 (1H, broad s), 7.38(2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.4 Hz), 6.75 (1H, s), 6.69 (1H, s),4.69 (2H, s), 1.82 (3H, s) ppm. ¹³C (CD₃OD, 100 MHz): δ 172.32, 164.16 &164.13, 142.41, 134.98, 131.02, 130.74, 124.43, 124.27, 121.90 & 121.86,116.85 & 116.81, 46.49, 22.67 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons:22.67; CH₂ carbons: 46.49; CH carbons: 131.02, 130.74, 124.27 & 124.09,116.85 & 116.81 ppm. HPLC: 8.077 min.

Example 71 Synthesis of4-([(4-chlorophenyl)-methylamino]methyl]-1H-pyrrole-2-carboxylic acid(192)

Synthesis of4-[[(4-chlorophenyl)-methylamino]methyl]-1H-pyrrole-2-carboxylic acidethyl ester (191)

4-chloro-N-methylaniline (0.225 mL, 1.86 mmol) was added to a stirring,room temperature solution of 4-formyl-1H-pyrrole-2-carboxylic acid ethylester (0.2585 g, 1.55 mmol) in 5% acetic acid in methanol under N₂.After stirring at room temperature for 30 minutes, sodiumcyanoborohydride (0.1585 g, 2.52 mmol) was added, and the reaction wasstirred at room temperature overnight. About 3 mL of saturated K₂CO₃were added, and the reaction was extracted twice with ethyl acetate. Thecombined organics were washed with saturated NaHCO₃ (˜4 mL) and brine(˜4 mL), then the combined organics were dried with Na₂SO₄, filtered andconcentrated en vacuo. The crude product was purified by silica gelchromatography (Combiflash column, 85:15 Hexanes:Ethyl acetate) toobtain 0.3419 g (76%) of4-{[(4-chlorophenyl)-methylamino]methyl]-1H-pyrrole-2-carboxylic acidethyl ester (191) as a light tan solid. Note: Starting material4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has an HPLC retentiontime=7.337 min. HPLC: 8.478 min.

Synthesis of4-(4-chlorophenyl)-methylamino]methyl]-1H-pyrrole-2-carboxylic acid(192)

4-{[(4-Chlorophenyl)-methylamino]methyl]-1H-pyrrole-2-carboxylic acidethyl ester (191) (0.3419 g, 1.17 mmol) was weighed out into a roundbottom flask. A stir bar, condenser, and septum are added, and the flaskwas purged with N₂. The ester was dissolved in EtOH (2.6 mL, 0.45 M),and then freshly prepared aqueous NaOH (0.1336 g, 1.0 mL H₂O) was addedwith stirring to the ester solution. The reaction flask was immediatelyimmersed in an oil bath preheated to 85° C., and the reaction was heatedand stirred under N₂ until judged complete by HPLC (15 min). The solventwas removed on the rotovap and the crude product was immediatelypurified by reverse phase preparative HPLC (45:55 H₂O with 0.05% TFA:CH₃CN with 0.05% TFA) to obtain pure4-{[(4-chlorophenyl)-methylamino]methyl]-1H-pyrrole-2-carboxylic acid(192).

¹H (CD₃OD, 400 MHz): δ 7.22 (2H, d, J=9.2 Hz), 6.95 (2H, d, J=9.2 Hz),6.81 (1H, d, J=1.5 Hz), 6.70 (1H, d, J=1.5 Hz), 4.43 (2H, s), 3.00 (3H,s) ppm. Partial ¹³C (CD₃OD, 100 MHz): δ 130.12, 124.02, 117.99, 116.47,52.37, 39.91 ppm. DEPT (CD₃OD, 100 MHz): CH₃ carbons: 14.48; CH₂carbons: 59.62, 23.41 and 23.39, 23.36 and 23.33, 23.16 and 23.13, 21.88and 21.86; CH carbons: 118.74 and 118.55 ppm.

Example 72 Synthesis of4-Benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (198)

Synthesis of 4-Oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid methylester (193)

A solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carbonitrile (4.5 g,28.1 mmol, prepared as described in Synth. Comm. 1995, 25, 507-514) inHCl gas saturated methanol (200 ml) was refluxed for 6 days. The solventwas removed under vacuum. The resulting product (3.5 g) was a 65/35mixture of expected ester and starting material as shown by NMRanalysis. This mixture was used in the next step without any furtherpurification.

Synthesis of4-Oxo-]-(2-trimethylsilyl-ethoxymethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid methyl ester(194)

A DMF (3 ml) solution of ester (500 mg, 2.6 mmol) was added to a cooled(0° C.) suspension of sodium hydride (114 mg, 60% in oil, 2.8 mmol) inDMF (2 ml). After 10 minutes, SEM-C1 (550 μl, 3.1 mmol) was added. Themixture was then stirred at room temperature for 2 h, then poured intoice-water and extracted with ethyl acetate. After concentration, theexpected compound was obtained as a crude oil (930 mg).

¹H NMR (CDCl₃, 400 MHz): δ 7.27 (1H, s), 5.78 (2H, s), 3.61 (2H, m),2.94 (2H, m), 2.50 (2H, m), 2.18 (2H, m), 0.92 (2H, m) ppm.

LC/MS: 60%

Synthesis of4-Benzylidene-]-(2-trimethylsilyl-ethoxymethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid methyl ester(195)

A dry THF solution (7 ml) of protected ester (900 mg, 2.78 mmol) wasadded to a solution of benzylmagnesium chloride (3.4 ml, 2M in THF, 6.8mmol) in THF (10 ml). After 2 h at room temperature, some morebenzylmagnesium chloride (1.7 ml, 2M in THF, 3.4 mmol) was added. Themixture was then refluxed for 1 night. Water was then added and thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to give the above titled compound (900 mg). LC/MS: 50%, m/z=397g/mol.

Synthesis of 4-Benzylidene-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid methyl ester (196)

Tetrabutylammonium fluoride (23 ml, 1M in THF, 23 mmol) was added over 5min to a solution of ester (900 mg, 2.26 mmol) in cooled THF (0° C.).The reaction mixture was then heated for 4 h at 80° C. After 48 h atroom temperature, the reaction mixture was partitioned between ether andwater. The organic layer was dried over MgSO4 and concentrated underreduced pressure to give the crude above titled compound. Silica gelchromatography (eluent cyclohexane/AcOEt: 80/20) afforded the purestarting material (100 mg) and the corresponding deprotected nitrile (80mg). The still protected pure ester (100 mg, 0.25 mmol) was mixed withTBAF (750 μl, 0.75 mmol). The THF was removed under vacuum. Afterconcentration, the reaction mixture was heated with ethylenediamine(0.25 ml) in DMF (1 ml) for 16 h. After concentration the above titledcompound was obtained as an oil (80 mg). LC/MS 76%, m/z=267 g/mol.

Synthesis of 4-Benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acidmethyl ester (197)

The saturated ester derivative was hydrogenated at normal pressure overPd in EtOH for 3 h. The catalyst was removed by filtration and thesolvent evaporated under reduced pressure to give the above titledcompound, which was purified by silica gel chromatography (eluentcyclohexane/CH₂Cl₂: 50/50). Yield: 20 mg. LC/MS: 60%, m/z=269 g/mol.

Synthesis of 4-Benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid(198)

Freshly prepared aq. NaOH (1M in H₂O, 0.8 ml, 0.8 mmol) was added atroom temperature to a stirred solution of ester (20 mg, 0.08 mmol) inEtOH (5 ml). The reaction was heated to 80° C. until the reaction wasjudged complete by TLC. The product was extracted with Et₂O, then theaqueous layer was made acid (pH=1) with the dropwise addition of 10% aq.HCl. The solid was filtered off and washed with water. The solid wasdried under vacuum overnight to give the above titled compound (19 mg).¹H NMR (CDCl₃, 400 MHz): δ 8.8 (1H, br s), 7.3-7.33 (2H, m), 7.2-7.26(3H, m), 6.81 (1H, s), 3.09 (1H, dd), 2.9 (1H, m), 2.55-2.65 (3H, m),1.9-2.0 (1H, m), 1.6-1.8 (2H, m), 1.3-1.4 (1H, m). LC/MS: 89%, m/z=255g/mol.

1. A compound of formula IA, or a pharmaceutically acceptable salt orsolvate thereof:

wherein R^(1a) and R_(2a) are independently selected from hydrogen,halo, nitro, alkyl, arylalkyl, alkylaryl, and XYR⁵; X and Y areindependently selected from O, S, NH, and (CR⁶R⁷)_(n); R³ is hydrogen,alkyl or M⁺; M is aluminum, calcium, lithium, magnesium, potassium,sodium, zinc or a mixture thereof; Z is N or CR⁴; R⁴ is selected fromhydrogen, halo, nitro, alkyl, arylalkyl, alkylaryl, and XYR⁵; R⁵ isselected from aryl, substituted aryl, heteroaryl and substitutedheteroaryl; R⁶ and R⁷ are independently selected from hydrogen andalkyl; n is an integer from 1 to 6; at least one of R^(1a) and R^(2a) isXYR⁵; and at least one of X and Y is (CR⁶R⁷)_(n); with the proviso thatformula 1A does not include 5-phenethyl-1H-pyrazole-3-carboxylic acid.2. A compound according to claim 1, wherein R³ is hydrogen.
 3. Acompound according to claim 1, wherein Z is N.
 4. A compound accordingto claim 1, wherein Z is CR⁴.
 5. A compound according to claim 1,wherein R^(1a) is hydrogen and R^(2a) is XYR⁵.
 6. A compound accordingto claim 1, wherein X and Y are CR⁶R⁷.
 7. A compound according to claim5, wherein R⁵ is substituted aryl.
 8. A compound according to claim 6,wherein R⁶ and R⁷are hydrogen.
 9. A compound according to claim 1,wherein the compound is selected from


10. A compound according to claim 1, wherein the compound is


11. A compound according to claim 1, wherein the compound is


12. (canceled)
 13. A method for treating schizophrenia, for treating orpreventing loss of memory and/or cognition associated with Alzheimer'sdisease, for treating ataxia, or for preventing loss of neuronalfunction characteristic of neurodegenerative diseases, said methodcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt or solvate thereof.

wherein R¹ and R² are independently selected from hydrogen, halo, nitro,alkyl, acyl, alkylaryl, arylalkyl, and XYR⁵; or R¹ and R², takentogether, form a 5, 6, 7 or 8-membered substituted or unsubstitutedcarbocyclic or heterocyclic group; X and Y are independently selectedfrom O, S, NH, and (CR⁶R⁷)_(n); R³ is hydrogen, alkyl or M⁺; M isaluminum, calcium, lithium, magnesium, potassium, sodium, zinc or amixture thereof; Z is N or CR⁴; R⁴ is from selected from hydrogen, halo,nitro, alkyl, alkylaryl, arylalkyl and XYR⁵; R⁵ is selected from aryl,substituted aryl, heteroaryl and substituted heteroaryl; R⁶ and R⁷ areindependently selected from hydrogen and alkyl; n is an integer from 1to 6; at least one of R¹, R² and R⁴ is other than hydrogen; and at leastone of X and Y is (CR⁶R⁷)_(n).
 14. (canceled)
 15. A method for treatingneuropathic pain comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt or solvate thereof:

wherein R¹ and R² are independently selected from hydrogen, halo, nitro,alkyl, acyl, alkylaryl, arylalkyl, and XYR⁵; or R¹ and R², takentogether, form a 5, 6, 7 or 8-membered substituted or unsubstitutedcarbocyclic or heterocyclic group; X and Y are independently selectedfrom O, S, NH, and (CR⁶R⁷)_(n); R³ is hydrogen, alkyl or M⁺; M isaluminum, calcium, lithium, magnesium, potassium, sodium, zinc or amixture thereof; Z is N or CR⁴; R⁴ is from selected from hydrogen, halo,nitro, alkyl, alkylaryl, arylalkyl and XYR⁵; R⁵ is selected from aryl,substituted aryl, heteroaryl and substituted heteroaryl; R⁶ and R⁷ areindependently selected from hydrogen and alkyl; n is an integer from 1to 6; at least one of R¹, R² and R⁴ is other than hydrogen; and at leastone of X and Y is (CR⁶R⁷)_(n).
 16. A method according to claim 15,wherein R¹ and R² are independently selected from hydrogen, halo, nitro,alkyl, arylalkyl, alkylaryl, and XYR⁵; at least one of R¹ and R² isXYR⁵; and at least one of X and Y is (CR⁶R⁷)_(n).
 17. A method accordingto claim 15, wherein R³ is hydrogen.
 18. A method according to claim 15,wherein Z is N.
 19. A method according to claim 15, wherein Z is CR⁴.20. A method according to claim 15, wherein n is 1 or
 2. 21. A methodaccording to claim 15, wherein X and Y are (CR⁶R⁷), and n is
 1. 22. Amethod according to claim 15, wherein R⁶ and R⁷ are hydrogen.
 23. Amethod according to claim 15, wherein R¹ is hydrogen and R² is XYR⁵. 24.A method according to claim 15, wherein R⁵ is substituted aryl.
 25. Amethod according to claim 15, wherein the compound of formula I isselected from


26. A method according to claim 15, wherein the compound of formula I is


27. A method according to claim 15, wherein the compound of formula I is


28. A method according to claim 15, additionally comprisingco-administering D-serine or cycloserine. 29-42. (canceled)